BACKGROUND Cyclin-dependent kinase 9(CDK9)expression and autophagy in colorectal cancer(CRC)tissues has not been widely studied.CDK9,a key regulator of transcription,may influence the occurrence and progression of CRC...BACKGROUND Cyclin-dependent kinase 9(CDK9)expression and autophagy in colorectal cancer(CRC)tissues has not been widely studied.CDK9,a key regulator of transcription,may influence the occurrence and progression of CRC.The expression of auto-phagy-related genes BECN1 and drug resistance factor ABCG2 may also play a role in CRC.Under normal physiological conditions,autophagy can inhibit tumorigenesis,but once a tumor forms,autophagy may promote tumor growth.Therefore,understanding the relationship between autophagy and cancer,partic-ularly how autophagy promotes tumor growth after its formation,is a key motivation for this research.AIM To investigate the relationship between CDK9 expression and autophagy in CRC,assess differences in autophagy between left and right colon cancer,and analyze the associations of autophagy-related genes with clinical features and prognosis.METHODS We collected tumor tissues and paracarcinoma tissues from colon cancer patients with liver metastasis to observe the level of autophagy in tissues with high levels of CDK9 and low levels of CDK9.We also collected primary tissue from left and right colon cancer patients with liver metastasis to compare the autophagy levels and the expression of BECN1 and ABCG2 in the tumor and paracarcinoma tissues.RESULTS The incidence of autophagy and the expression of BECN1 and ABCG2 were different in left and right colon cancer,and autophagy might be involved in the occurrence of chemotherapy resistance.Further analysis of the rela-tionship between the expression of autophagy-related genes CDK9,ABCG2,and BECN1 and the clinical features and prognosis of colorectal cancer showed that the high expression of CDK9 indicated a poor prognosis in colorectal cancer.CONCLUSION This study laid the foundation for further research on the combination of CDK9 inhibitors and autophagy inhibitors in the treatment of patients with CRC.展开更多
Introduction Neutrophils,a crucial component of the innate immune system,are the most abundant bone marrow-derived eukaryotic cell in human blood.The functional importance of neutrophils is often overlooked because ne...Introduction Neutrophils,a crucial component of the innate immune system,are the most abundant bone marrow-derived eukaryotic cell in human blood.The functional importance of neutrophils is often overlooked because neutrophils are short-lived,terminally differentiated,and do not proliferate.Although traditionally considered anti-bacterial cells,research has demonstrated the multifaceted roles of neutrophils in cancer.Studies have suggested that neutrophils with normal functions co-exist with pathologically activated neutrophils that support tumorprogression and metastasis in the context of cancer.展开更多
Vascular endothelial growth factor(VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown...Vascular endothelial growth factor(VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown that VEGF also plays a vital role in the immune environment. In addition to the traditional growth factor role of VEGF and VEGF receptors(VEGFRs), they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis. Dendritic cells(DCs), macrophages, and lymphocytes further express certain types of VEGF receptors.VEGF can be secreted as well by tumor cells through the autocrine pathway and can stimulate the function of cancer stemness.This review will provide a paradigm shift in our understanding of the role of VEGF/VEGFR signaling in the immune and cancer environment.展开更多
Objective: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase(PI3K) and mitogen-activated protein kinase(MAPK) pathways on the clinic...Objective: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase(PI3K) and mitogen-activated protein kinase(MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) treatment of non-small cell lung cancer(NSCLC) patients.Methods: Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3 CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios(ORs) for objective response rate(ORR) and hazard ratios(HRs) for progression-free survival(PFS) and overall survival(OS) were calculated.Results: Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval(CI), 0.13-0.35], shorter PFS(HR =1.56; 95% CI, 1.27-1.92), and shorter OS(HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3 CA significantly predicted shorter OS(HR =1.83; 95% CI, 1.05-3.20), showed poor ORR(OR =0.70; 95% CI, 0.22-2.18), and shorter PFS(HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.Conclusion: K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFRTKIs. PIK3 CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3 CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.展开更多
Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abn...Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide(M3G)levels.Hence,the effects of M3G on tumor progression are worth studying.Methods:The effects of M3G on PD-L1 expressions in human non-small cell lung cancer(NSCLC)cell lines were first evaluated.Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot.The effects of M3G on human cytotoxic T lymphocytes(CTL)cytotoxicity and INF-γrelease was also detected.Finally,the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model,and the effects of M3G on tumor growth and metastasis were determined.Results:M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner(P<0.05).M3G activated the PI3 K and the NFκB signaling pathways,and this effect was antagonized by a TLR4 pathway inhibitor.A PI3 K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation.M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ.Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment.Conclusions:M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3 K signaling pathway,thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.展开更多
At the beginning of the last century,Dr.William Coley introduced“Coley’s toxin”to the scientific community after observing that a small number of patients with sarcoma with infections developed spontaneous tumor re...At the beginning of the last century,Dr.William Coley introduced“Coley’s toxin”to the scientific community after observing that a small number of patients with sarcoma with infections developed spontaneous tumor regression.“Coley’s toxin”consisted of bacteria or bacterial products and achieved a durable response in a small group of patients with cancer,most of whom had inoperable sarcoma.However,this response was usually unpredictable because of the lack of understanding of the immune response at that time.Since then,researchers have continued to study the relationship between cancer and the host immune system,and the discovery of“Coley’s toxin”marked the beginning of cancer immunotherapy^(1).展开更多
A postmenopausal patient with a diagnosis of estrogen receptor(ER)(+), progesterone receptor(PR)(+), and human epidermal growth factor receptor-2(HER2)(-) breast cancer was reported. The patient refused surgery and wa...A postmenopausal patient with a diagnosis of estrogen receptor(ER)(+), progesterone receptor(PR)(+), and human epidermal growth factor receptor-2(HER2)(-) breast cancer was reported. The patient refused surgery and was resistant to conventional chemotherapy regimens. Computed tomography and the circulating tumor cell test indicated that the patient's tumor burden increased rapidly even after several chemotherapy sessions. Multiple genetic aberrances in the phosphatidylinositol3-kinases(PI3 K) signaling pathway were detected via next-generation sequencing(NGS)-based liquid biopsy, including a p. G1007 R missense mutation in exon 21 of PIK3 CA(33.61%), a p.L70 fs frameshift mutation in exon 3 of phosphatase and tension homolog deleted on chromosome ten(PTEN)(49.14%), and a p. D1542 Y missense mutation in exon 32 of mammalian target of rapamycin(m TOR)(1.66%). Therefore, only the m TOR inhibitor everolimus was administered to the patient. Partial remission(PR) was observed after 2 months, and sustained stable disease(SD) was observed after a year and a half. Subsequent sequencing showed that the mutation ratio of PIK3 CA decreased to 4.17%, and that the PTEN and m TOR mutations disappeared, which revealed the significant curative effect of everolimus. We report the first case of successful monotherapy treatment using everolimus in a patient with advanced breast cancer bearing mutations in genes involved in the PI3 K/ARK/m TOR signaling pathway. The success of this case highlights the invaluable clinical contribution of NGS-based liquid biopsy, as it successfully provided an optimal therapeutic target for the patient with advanced breast cancer.展开更多
The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.Howeve...The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.展开更多
On March 5th, a novel immunosuppressive molecule,Siglec-15, was reported in Nature Medicine by Professor Lieping Chen1. Siglec-15 was reported in a wide variety of tumors. The molecule is not a simple replica of PD-1/...On March 5th, a novel immunosuppressive molecule,Siglec-15, was reported in Nature Medicine by Professor Lieping Chen1. Siglec-15 was reported in a wide variety of tumors. The molecule is not a simple replica of PD-1/PD-L1.Rather, the expressions of Siglec-15 and PD-L1 are mutually exclusive1, suggesting that Siglec-15 antibodies may be effective on tumors that are not responsive to anti-PD-1/PDL1 therapy. Siglec-15 potentially serves as a complementary therapeutic target and offers alternative treatments for many anti-PD-l/PD-Ll therapy unresponsive patients. This discovery generated a huge response.展开更多
Objective:The E3 ligase,CRL4,plays diverse roles in different cellular processes,such as DNA damage,transcriptional regulation,cell cycle progression,and cell apoptosis.Our previous study showed that CUL4A and CUL4B h...Objective:The E3 ligase,CRL4,plays diverse roles in different cellular processes,such as DNA damage,transcriptional regulation,cell cycle progression,and cell apoptosis.Our previous study showed that CUL4A and CUL4B had a strong association with tobacco smoking risk in lung squamous cell carcinoma(SCC)and small cell lung carcinoma(SCLC).This study aimed to define the potential mechanism underlying the roles of CUL4A and CUL4B in the development of SCC and SCLC.Methods:We determined the role of CUL4A and CUL4B in the cell cycle and apoptosis of SCC and SCLC,and identified the key apoptosis-related gene involved in the oncogenic activity of CUL4B by Western blot,immunohistochemical staining,flow cytometry,and enzyme inhibition experiments.Results:We found that depletion of CUL4A and CUL4B reduced the proliferation of SCC and SCLC cells.cUL4Aknockdown but not CUL4Bknockdown arrested cells in Gl phase while upregulating P21 and cU L4Bknockdown promoted cell apoptosis through upregulation o f FOXO3A.Accordingly,CUL4B decreased FO X03A expression by activating the ERK signaling pathway and mediating FOXO3A degradation via the ubiquitin-proteasome pathway.Conclusions:These results identified the function of E3 ligase CRL4 in regulating SCC and SCLC cell proliferation,which provides a potential strategy for cancer therapy by targeting FOXO3A and the E3 ligase,CRL4.展开更多
Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatm...Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated.The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC.Methods:Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital.We performed whole-exome sequencing(WES)on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC,and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment.Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance.WES and RNA-seq data between lung squamous cell carcinoma(SCC)and adenocarcinoma(Aden)were analyzed and compared.Results:The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS,as analyzed by multivariate Cox proportional hazard regression(P=0.031).The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment.Relatively low expression of HLA class II genes and checkpoint molecules,and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC.Conclusions:Coordinated suppression of the expression of HLA class II genes and checkpoint molecules,as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden.展开更多
Objective:To explore the expression and clinical significance of RACGAP1 gene in hepatocellular carcinoma.Methods:Data about RACGAP1 gene and clinic pathological data in liver cancer were retrieved from The Cancer Gen...Objective:To explore the expression and clinical significance of RACGAP1 gene in hepatocellular carcinoma.Methods:Data about RACGAP1 gene and clinic pathological data in liver cancer were retrieved from The Cancer Genome Atlas(TCGA).The relationship between the expression of RACGAP1 gene and clinic pathological parameters,and prognosis were analyzed by R 2.15.3 software.The association between RACGAP1 gene expression and prognosis of liver cancer patients was analyzed by Kaplan-Meier survival function analysis and Cox regression analysis.Results:TCGA database was used to collect 235 cases of liver cancer with clinical pathological parameters and their corresponding RACGAP1 expression levels.After the incomplete cases and those with no detailed pathological parameters were excluded,and it was found that RACGAP1 was highly expressed in liver cancer tissues.Meanwhile,the expression of RACGAP1 in patients with liver cancer in the TCGA tumor database was further analyzed with the matching clinical data parameters.The expression level of RACGAP1 was significantly correlated with the pathological grade and T stage of liver cancer patients(all P<0.05),but was not significantly correlated with American Joint Committee on Cancer(AJCC)pathological stage and gender(P>0.05).There was a significant correlation between RACGAP1 expression level and overall survival(OS)in patients with liver cancer(P<0.05),and the overall survival time of patients with low expression was better than that of patients with high expression(P<0.05).Cox regression was used to analyze the correlation between T stage,M stage,N stage and RACGAP1 expression in patients with hepatocellular carcinoma(HCC),and RACGAP1 became an independent prognostic factor in patients with HCC(P<0.05).Conclusion:Based on the tumor-related gene information in the public database TCGA,RACGAP1 gene is highly expressed in liver cancer tissues and becomes an independent prognostic factor of liver cancer,which is expected to become an important therapeutic target of drug therapy for liver cancer.展开更多
Objective:To assess the clinical outcomes and toxicities of once daily(QD)simultaneous dose reduction intensity-modulated radiotherapy(SDR-IMRT-QD;SDR-QD)versus conventional QD IMRT(C-QD)and twice daily(BID)IMRT in pa...Objective:To assess the clinical outcomes and toxicities of once daily(QD)simultaneous dose reduction intensity-modulated radiotherapy(SDR-IMRT-QD;SDR-QD)versus conventional QD IMRT(C-QD)and twice daily(BID)IMRT in patients with limited-stage small cell lung cancer(LS-SCLC).Methods:After propensity score matching(PSM),a retrospective analysis involving 300 patients with LS-SCLC treated using SDR-QD,C-QD,or BID was performed from January 1,2014 to December 31,2019.The prescribed irradiation dose in the SDR-QD cohort was 60 Gy/PGTV and 54 Gy/PTV QD.The radiation dose was 60 Gy for both PGTV and PTV QD in the C-QD cohort.The radiation dose was 45 Gy for both PGTV and PTV in the BID cohort.Toxicities,short-term effects,and survival outcomes were recorded.A meta-analysis on the protective effects of pharmaceuticals for cardiac toxicities induced by anti-tumor therapy was performed.Results:The median overall survival time(MST)in the 3 cohorts were 32.7 months(SDR-QD),26.3 months(C-QD),and 33.6 months(BID);the differences between groups were statistically significant.Lower toxicities and doses to organs-at-risk(OARs)occurred in the SDR-QD and BID cohorts.Further,the cardiac dose dosimetric parameter Vheart40 was negatively associated with survival(r=-0.35,P=0.007).A Vheart40 value of 16.5%was recommended as a cut-off point,which yielded 54.7%sensitivity and 85.7%specificity for predicting negative survival outcomes.The meta-analysis indicated that pharmaceuticals significantly reduced the cardiac toxicities induced by chemotherapy,but not radiotherapy.Conclusions:SDR-QD was shown to have similar toxicities and survival compared with BID,but fewer toxicities and better survival than C-QD.In addition,cardiac dose exposure was negatively associated with survival.Thus,16.5%of the cardiac dosimetric parameter Vheart40 is recommended as the cut-off point,and a Vheart40>16.5%predicts poor survival.展开更多
Exhausted T cells are a group of dysfunctional T cells,which are present in chronic infections or tumors.The most significant characteristics of exhausted T cells are attenuated effector cytotoxicity,reduced cytokine ...Exhausted T cells are a group of dysfunctional T cells,which are present in chronic infections or tumors.The most significant characteristics of exhausted T cells are attenuated effector cytotoxicity,reduced cytokine production,and upregulation of multiple inhibitory molecular receptors(e.g.,PD-1,TIM-3,and LAG-3).The intracellular metabolic changes,altered expression of transcription factors,and a unique epigenetic landscape constitute the exhaustion program.Recently,researchers have made progress in understanding exhausted T cells,with the definition and identification of exhausted T cells changing from phenotypebased to being classified at the transcriptional and epigenetic levels.Recent studies have revealed that exhausted T cells can be separated into two subgroups,namely TCF1^(+)PD-1^(+)progenitor-like precursor exhausted cells and TCF1-PD-1^(+)terminally differentiated exhausted T cells.Moreover,the progenitor-like precursor cell population may be a subset of T cells that can respond to immunotherapy.Studies have also found that TOX initiates and dominates the development of exhausted T cells at the transcriptional and epigenetic levels.TOX also maintains T cell survival and may affect decisions regarding treatment strategies.In this review,we discuss the latest developments in T cell exhaustion in regards to definitions,subpopulations,development mechanisms,differences in diverse diseases,and treatment prospects for exhausted T cells.Furthermore,we hypothesize that the epigenetic state regulated by TOX might be the key point,which can determine the reversibility of exhaustion and the efficacy of immunotherapy.展开更多
Objective:Distinguishing immune-related adverse events(irAEs)caused by immune checkpoint inhibitors(ICIs)from the AEs caused by chemotherapy,targeted therapy,or infection is highly difficult.This study offers new insi...Objective:Distinguishing immune-related adverse events(irAEs)caused by immune checkpoint inhibitors(ICIs)from the AEs caused by chemotherapy,targeted therapy,or infection is highly difficult.This study offers new insights into evaluating the diagnosis,differential diagnostic,and prognostic value of ferritin for irAEs induced by ICIs.Methods:From December 1,2018,to April 1,2019,we examined 318 patients with malignant tumors who received serum ferritin monitoring.The cohort comprised 231 patients treated with PD-1 inhibitor or combination with chemotherapy,and 87 patients treated with chemotherapy.Of the 231 patients,90 had irAEs(irAE group),70 had non-irAEs(non-irAE group),67 had no AEs(no irAE-non irAE group),and 4 had unclassified AEs.In the 87 patients,60 had AEs(AE group),and 27 had no AEs(no AE group).Statistical analyses were conducted with nonparametric Mann-Whitney tests.Results:At the onset of AEs in the irAE group,ferritin(normal range,35–150μg/L)rose to a median of 927μg/L(range,117–17,825μg/L)from 86μg/L at baseline(range,29–421μg/L)(P<0.001).Ferritin levels at the onset of AEs in the irAE group were significantly higher than those in the non-irAE group(median,81μg/L;range,32–478μg/L)(P<0.001)and the AE group(median,103μg/L;range,23–712μg/L)(P<0.001).After treatment in the irAE group,ferritin continuously decreased to a normal range in recovered patients,showed no significant changes in stable patients,and continued to rise in patients who died.Conclusions:Ferritin can be used as a diagnostic,differential diagnostic,and prognostic marker for irAEs in patients treated with ICIs.展开更多
Tertiary lymphoid structures(TLSs)are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions,including infection,autoimmune disease,and cance...Tertiary lymphoid structures(TLSs)are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions,including infection,autoimmune disease,and cancer.In the tumor microenvironment(TME),the structures of TLSs,including B-cell-and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against cancers.Numerous studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer patients.It was shown that welldeveloped TLSs characterized by mature B cells synthesized tumor specific antibodies,which were considered as specific markers for a good prognosis.However,there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor responses.These factors include dysfunctional B cells,regulatory T cells,and T follicular regulatory cells.The complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs;it is therefore essential to fully understand the function and influencing factors in TLSs.It has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer immunotherapies.In this review,we focused on recent advances in TLSs in human solid tumors,including structural characteristics and classes,antitumor mechanisms,immunosuppressive factors,and TLSbased therapeutic approaches.展开更多
Objective: More than half of human glioblastomas show EGFR gene amplification and mutation, but EGFR inhibitors have not been effective in treating EGFR-positive glioblastoma patients.The mechanism behind this type of...Objective: More than half of human glioblastomas show EGFR gene amplification and mutation, but EGFR inhibitors have not been effective in treating EGFR-positive glioblastoma patients.The mechanism behind this type of primary resistance is not well understood.The aim of this study was to investigate gefitinib resistance in glioblastoma, and explore ways to circumvent this significant clinical problem.Methods: MTT method was used to test the cell viability after EGFR-positive glioblastoma cells were treated with indicated drugs;real-time quantitative PCR method was included to detect the TNFα mRNA levels in glioma tissues and cell lines.ELISA was introduced to measure the TNFα protein levels in cell culture supernatant of glioblastoma cells treated with gefitinib.Western blot was used to detect the activity change of intracellular kinases in drug-treated glioblastoma cells.Two mouse xenograft tumor models were carried out to evaluate the in vivo effects of a combination of EGFR and TNFα inhibitors.Results: We found that glioblastoma resistance to gefitinib may be mediated by an adaptive pro-survival TNFα-JNK-Axl signaling axis, and that high TNFα levels in the glioblastoma microenvironment may further intensify primary resistance.A combination of the TNFα-specific small-molecule inhibitor C87 and gefitinib significantly enhanced the sensitivity of glioblastoma cells to gefitinib in vitro and in vivo.Conclusions: Our findings provide a possible explanation for the primary resistance of glioblastoma to EGFR inhibitors and suggest that dual blockade of TNFα and EGFR may be a viable therapeutic strategy for the treatment of patients with chemotherapy-refractory advanced glioblastoma.展开更多
Objective:Lung cancer is the most common cause of cancer-related deaths worldwide.Somatic copy number alterations(SCNAs)have been used to predict responses to therapies in many cancers,including lung cancer.However,li...Objective:Lung cancer is the most common cause of cancer-related deaths worldwide.Somatic copy number alterations(SCNAs)have been used to predict responses to therapies in many cancers,including lung cancer.However,little is known about whether they are predictive of radiotherapy outcomes.We aimed to understand the prognostic value and biological functions of SCNAs.Methods:We analyzed the correlation between SCNAs and clinical outcomes in The Cancer Genome Atlas data for 486 patients with non-small cell lung cancer who received radiotherapy.Gene set enrichment analyses were performed to investigate the potential mechanisms underlying the roles of SCNAs in the radiotherapy response.Our results were validated in 20 patients with lung adenocarcinoma(LUAD)receiving radiotherapy.Results:SCNAs were a better predictor of progression-free survival(PFS)in LUAD(P=0.024)than in lung squamous carcinoma(P=0.18)in patients treated with radiotherapy.Univariate and multivariate regression analyses revealed the superiority of SCNAs in predicting PFS in patients with LUAD.Patients with stage I cancer and low SCNA levels had longer PFS than those with high SCNA levels(P=0.022).Our prognostic nomogram also showed that combining SCNAs and tumor/node/metastasis provided a better model for predicting long-term PFS.Additionally,high SCNA may activate the cell cycle pathway and induce tumorigenesis.Conclusions:SCNAs may be used to predict PFS in patients with early-stage LUAD with radiotherapy,in combination with TNM,with the aim of predicting long-term PFS.Therefore,SCNAs are a novel predictive biomarker for radiotherapy in patients with LUAD.展开更多
Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods ...Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation.However,the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown.We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12,IL-15,and IL-18,and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity.On the basis of our hypothesis,we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention.Methods:Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets.Single-cell RNA sequencing(scRNA-seq)plus TotalSeq™technology was used to track the heterogeneity of NK cells during the induction of trained immunity.Results:Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity.Therefore,we used scRNA-seq plus TotalSeq™technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+NK cells.Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells.We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+NK cells had faster cell cycles and an enhanced trained phenotype,and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells.These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity.Conclusions:Our work revealed human NK heterogeneity in the induction of trained immunity,identified the precursor subset for trained NK cells,and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells.展开更多
Dear Editor,Cytokine-induced killer(CIK)cells have been recognized as a new type of anti-tumor effector cells.CIK cells are a mixture of T lymphocytes.Among them,CD3+/CD56+T cells,which are rare in uncultured peripher...Dear Editor,Cytokine-induced killer(CIK)cells have been recognized as a new type of anti-tumor effector cells.CIK cells are a mixture of T lymphocytes.Among them,CD3+/CD56+T cells,which are rare in uncultured peripheral blood,are the main effector cells.CIK cells can proliferate rapidly in vitro,with stronger antitumor activity,broader target tumor spectrum,and lower adverse effect than other reported antitumor effector cells.1 Their ease of production in vitro and antitumor potential have made them suitable candidates for cell therapy regimens in solid and hematopoietic tumor treatments.1,2 Our previous retrospective study showed that the median progression-free survival(PFS)and overall survival(OS)in untreated,advanced non-small-cell lung cancer(NSCLC)patients who received CIK cell immunotherapy plus chemotherapy(13 and 24 months,respectively)were significantly longer than in those who received chemotherapy alone(6 and 10 months,respectively).2 But so far,there is no prospective,multicenter clinical study in lung cancer.Based on our previous study,we designed this randomized,multicenter,open-label trial to further evaluate the clinical efficacy of CIK cell immunotherapy plus chemotherapy in patients with advanced squamous NSCLC(ClinicalTrials.gov number,NCT01631357).展开更多
基金the Science and Technology Development Fund of Tianjin Education Commission for Higher Education,No.2020KJ133Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-009A.
文摘BACKGROUND Cyclin-dependent kinase 9(CDK9)expression and autophagy in colorectal cancer(CRC)tissues has not been widely studied.CDK9,a key regulator of transcription,may influence the occurrence and progression of CRC.The expression of auto-phagy-related genes BECN1 and drug resistance factor ABCG2 may also play a role in CRC.Under normal physiological conditions,autophagy can inhibit tumorigenesis,but once a tumor forms,autophagy may promote tumor growth.Therefore,understanding the relationship between autophagy and cancer,partic-ularly how autophagy promotes tumor growth after its formation,is a key motivation for this research.AIM To investigate the relationship between CDK9 expression and autophagy in CRC,assess differences in autophagy between left and right colon cancer,and analyze the associations of autophagy-related genes with clinical features and prognosis.METHODS We collected tumor tissues and paracarcinoma tissues from colon cancer patients with liver metastasis to observe the level of autophagy in tissues with high levels of CDK9 and low levels of CDK9.We also collected primary tissue from left and right colon cancer patients with liver metastasis to compare the autophagy levels and the expression of BECN1 and ABCG2 in the tumor and paracarcinoma tissues.RESULTS The incidence of autophagy and the expression of BECN1 and ABCG2 were different in left and right colon cancer,and autophagy might be involved in the occurrence of chemotherapy resistance.Further analysis of the rela-tionship between the expression of autophagy-related genes CDK9,ABCG2,and BECN1 and the clinical features and prognosis of colorectal cancer showed that the high expression of CDK9 indicated a poor prognosis in colorectal cancer.CONCLUSION This study laid the foundation for further research on the combination of CDK9 inhibitors and autophagy inhibitors in the treatment of patients with CRC.
基金supported by the National Natural Science Foundation of China (U20A20375,82372779,82373279,and 82373283)the Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A)。
文摘Introduction Neutrophils,a crucial component of the innate immune system,are the most abundant bone marrow-derived eukaryotic cell in human blood.The functional importance of neutrophils is often overlooked because neutrophils are short-lived,terminally differentiated,and do not proliferate.Although traditionally considered anti-bacterial cells,research has demonstrated the multifaceted roles of neutrophils in cancer.Studies have suggested that neutrophils with normal functions co-exist with pathologically activated neutrophils that support tumorprogression and metastasis in the context of cancer.
基金supported by grants from the key program of the National Basic Research Program of China (973 program) (Grant No. 2012CB9333004)the National Natural Science Foundation of China (Grant No. 81401888)
文摘Vascular endothelial growth factor(VEGF) is primarily known as a proangiogenic factor and is one of the most important growth and survival factors affecting the vascular endothelium. However, recent studies have shown that VEGF also plays a vital role in the immune environment. In addition to the traditional growth factor role of VEGF and VEGF receptors(VEGFRs), they have a complicated relationship with various immune cells. VEGF also reportedly inhibits the differentiation and function of immune cells during hematopoiesis. Dendritic cells(DCs), macrophages, and lymphocytes further express certain types of VEGF receptors.VEGF can be secreted as well by tumor cells through the autocrine pathway and can stimulate the function of cancer stemness.This review will provide a paradigm shift in our understanding of the role of VEGF/VEGFR signaling in the immune and cancer environment.
基金supported by Key Projects in the National Science & Technology Pillar Program (Grant No. 2013ZX09303001, 2015BAI12B12, and 2015BAI12B15)National Natural Science Foundation of China (Grant No. 81472473 and 81272360)Tianjin Municipal Commission of Science & Technology Key Research Program (Grant No.13ZCZCSY20300)
文摘Objective: A meta-analysis was performed to augment the insufficient data on the impact of mutative EGFR downstream phosphatidylinositol-3-kinase(PI3K) and mitogen-activated protein kinase(MAPK) pathways on the clinical efficiency of epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI) treatment of non-small cell lung cancer(NSCLC) patients.Methods: Network databases were explored in April, 2015. Papers that investigated the clinical outcomes of NSCLC patients treated with EGFR-TKIs according to the status of K-ras and/or PIK3 CA gene mutation were included. A quantitative meta-analysis was conducted using standard statistical methods. Odds ratios(ORs) for objective response rate(ORR) and hazard ratios(HRs) for progression-free survival(PFS) and overall survival(OS) were calculated.Results: Mutation in K-ras significantly predicted poor ORR [OR =0.22; 95% confidence interval(CI), 0.13-0.35], shorter PFS(HR =1.56; 95% CI, 1.27-1.92), and shorter OS(HR =1.59; 95% CI, 1.33-1.91) in NSCLC patients treated with EGFR-TKIs. Mutant PIK3 CA significantly predicted shorter OS(HR =1.83; 95% CI, 1.05-3.20), showed poor ORR(OR =0.70; 95% CI, 0.22-2.18), and shorter PFS(HR =1.79; 95% CI, 0.91-3.53) in NSCLC patients treated with EGFR-TKIs.Conclusion: K-ras mutation adversely affected the clinical response and survival of NSCLC patients treated with EGFRTKIs. PIK3 CA mutation showed similar trends. In addition to EGFR, adding K-ras and PIK3 CA as routine gene biomarkers in clinical genetic analysis is valuable to optimize the effectiveness of EGFR-TKI regimens and identify optimal patients who will benefit from EGFR-TKI treatment.
基金supported by the Science&Technology Development Fund of Tianjin Education Commission for Higher Education,Tianjin,China(Grant No.2017KJ200)。
文摘Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient outcomes.The long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide(M3G)levels.Hence,the effects of M3G on tumor progression are worth studying.Methods:The effects of M3G on PD-L1 expressions in human non-small cell lung cancer(NSCLC)cell lines were first evaluated.Activation of TLR4 downstream pathways after M3G treatment was then determined by Western blot.The effects of M3G on human cytotoxic T lymphocytes(CTL)cytotoxicity and INF-γrelease was also detected.Finally,the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model,and the effects of M3G on tumor growth and metastasis were determined.Results:M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner(P<0.05).M3G activated the PI3 K and the NFκB signaling pathways,and this effect was antagonized by a TLR4 pathway inhibitor.A PI3 K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation.M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ.Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor microenvironment.Conclusions:M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3 K signaling pathway,thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.
文摘At the beginning of the last century,Dr.William Coley introduced“Coley’s toxin”to the scientific community after observing that a small number of patients with sarcoma with infections developed spontaneous tumor regression.“Coley’s toxin”consisted of bacteria or bacterial products and achieved a durable response in a small group of patients with cancer,most of whom had inoperable sarcoma.However,this response was usually unpredictable because of the lack of understanding of the immune response at that time.Since then,researchers have continued to study the relationship between cancer and the host immune system,and the discovery of“Coley’s toxin”marked the beginning of cancer immunotherapy^(1).
文摘A postmenopausal patient with a diagnosis of estrogen receptor(ER)(+), progesterone receptor(PR)(+), and human epidermal growth factor receptor-2(HER2)(-) breast cancer was reported. The patient refused surgery and was resistant to conventional chemotherapy regimens. Computed tomography and the circulating tumor cell test indicated that the patient's tumor burden increased rapidly even after several chemotherapy sessions. Multiple genetic aberrances in the phosphatidylinositol3-kinases(PI3 K) signaling pathway were detected via next-generation sequencing(NGS)-based liquid biopsy, including a p. G1007 R missense mutation in exon 21 of PIK3 CA(33.61%), a p.L70 fs frameshift mutation in exon 3 of phosphatase and tension homolog deleted on chromosome ten(PTEN)(49.14%), and a p. D1542 Y missense mutation in exon 32 of mammalian target of rapamycin(m TOR)(1.66%). Therefore, only the m TOR inhibitor everolimus was administered to the patient. Partial remission(PR) was observed after 2 months, and sustained stable disease(SD) was observed after a year and a half. Subsequent sequencing showed that the mutation ratio of PIK3 CA decreased to 4.17%, and that the PTEN and m TOR mutations disappeared, which revealed the significant curative effect of everolimus. We report the first case of successful monotherapy treatment using everolimus in a patient with advanced breast cancer bearing mutations in genes involved in the PI3 K/ARK/m TOR signaling pathway. The success of this case highlights the invaluable clinical contribution of NGS-based liquid biopsy, as it successfully provided an optimal therapeutic target for the patient with advanced breast cancer.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81974416 and 81872166)the Key Project of Tianjin Health Industry(Grant No.15KG145).
文摘The programmed cell death-1(PD-1)/programmed cell death ligand 1(PD-L1)signaling pathway is an important mechanism in tumor immune escape,and expression of PD-L1 on tumor cells has been reported more frequently.However,accumulating evidence suggests that PD-1/PD-L1 is also widely expressed on immune cells,and that regulation is also critical for tumor immune responses.In this review,we emphasized that under solid tumor conditions,the immunoregulatory effects of immune cells expressing PD-1 or PD-L1,affected the prognoses of cancer patients.Therefore,a better understanding of the mechanisms that regulate PD-1 or PD-L1 expression on immune cells would provide clear insights into the increased efficacy of anti-PD antibodies and the development of novel tumor immunotherapy strategies.
文摘On March 5th, a novel immunosuppressive molecule,Siglec-15, was reported in Nature Medicine by Professor Lieping Chen1. Siglec-15 was reported in a wide variety of tumors. The molecule is not a simple replica of PD-1/PD-L1.Rather, the expressions of Siglec-15 and PD-L1 are mutually exclusive1, suggesting that Siglec-15 antibodies may be effective on tumors that are not responsive to anti-PD-1/PDL1 therapy. Siglec-15 potentially serves as a complementary therapeutic target and offers alternative treatments for many anti-PD-l/PD-Ll therapy unresponsive patients. This discovery generated a huge response.
基金The National Natural Science Foundation of China(Grant No.81772620 and 31471341)the Key Science and Technology Project of Tianjin Chronic Disease Prevention and Control(Grant No.17XXMFSY00130)the National Science and Technology Major Project(Grant No.2018ZX09201-015).
文摘Objective:The E3 ligase,CRL4,plays diverse roles in different cellular processes,such as DNA damage,transcriptional regulation,cell cycle progression,and cell apoptosis.Our previous study showed that CUL4A and CUL4B had a strong association with tobacco smoking risk in lung squamous cell carcinoma(SCC)and small cell lung carcinoma(SCLC).This study aimed to define the potential mechanism underlying the roles of CUL4A and CUL4B in the development of SCC and SCLC.Methods:We determined the role of CUL4A and CUL4B in the cell cycle and apoptosis of SCC and SCLC,and identified the key apoptosis-related gene involved in the oncogenic activity of CUL4B by Western blot,immunohistochemical staining,flow cytometry,and enzyme inhibition experiments.Results:We found that depletion of CUL4A and CUL4B reduced the proliferation of SCC and SCLC cells.cUL4Aknockdown but not CUL4Bknockdown arrested cells in Gl phase while upregulating P21 and cU L4Bknockdown promoted cell apoptosis through upregulation o f FOXO3A.Accordingly,CUL4B decreased FO X03A expression by activating the ERK signaling pathway and mediating FOXO3A degradation via the ubiquitin-proteasome pathway.Conclusions:These results identified the function of E3 ligase CRL4 in regulating SCC and SCLC cell proliferation,which provides a potential strategy for cancer therapy by targeting FOXO3A and the E3 ligase,CRL4.
基金This work was supported by the National Key Technologies R&D Program(Grant No.2015BAI12B12)the National Key R&D Program(Grant No.2018YFC1313400)+2 种基金grants from the National Natural Science Foundation of China(Grant Nos.81802873 and 81672697)the Natural Science Foundation of Tianjin(Grant No.18JCQNJC81300)the Tianjin Municipal Education Commission Program(Grant No.2017KJ197).
文摘Objective:Patients with non–small cell lung cancer(NSCLC)respond differently to cytokine-induced killer cell(CIK)treatment.Therefore,potential prognostic markers to identify patients who would benefit from CIK treatment must be elucidated.The current research aimed at identifying predictive prognostic markers for efficient CIK treatment of patients with NSCLC.Methods:Patients histologically diagnosed with NSCLC were enrolled from the Tianjin Medical University Cancer Institute and Hospital.We performed whole-exome sequencing(WES)on the tumor tissues and paired adjacent benign tissues collected from 50 patients with NSCLC,and RNA-seq on tumor tissues of 17 patients with NSCLC before CIK immunotherapy treatment.Multivariate Cox proportional hazard regression analysis was used to analyze the association between clinical parameters and prognostic relevance.WES and RNA-seq data between lung squamous cell carcinoma(SCC)and adenocarcinoma(Aden)were analyzed and compared.Results:The pathology subtype of lung cancer was the most significantly relevant clinical parameter associated with DFS,as analyzed by multivariate Cox proportional hazard regression(P=0.031).The patients with lung SCC showed better CIK treatment efficacy and extended DFS after CIK treatment.Relatively low expression of HLA class II genes and checkpoint molecules,and less immunosuppressive immune cell infiltration were identified in the patients with lung SCC.Conclusions:Coordinated suppression of the expression of HLA class II genes and checkpoint molecules,as well as less immune suppressive cell infiltration together contributed to the better CIK treatment efficacy in lung SCC than lung Aden.
文摘Objective:To explore the expression and clinical significance of RACGAP1 gene in hepatocellular carcinoma.Methods:Data about RACGAP1 gene and clinic pathological data in liver cancer were retrieved from The Cancer Genome Atlas(TCGA).The relationship between the expression of RACGAP1 gene and clinic pathological parameters,and prognosis were analyzed by R 2.15.3 software.The association between RACGAP1 gene expression and prognosis of liver cancer patients was analyzed by Kaplan-Meier survival function analysis and Cox regression analysis.Results:TCGA database was used to collect 235 cases of liver cancer with clinical pathological parameters and their corresponding RACGAP1 expression levels.After the incomplete cases and those with no detailed pathological parameters were excluded,and it was found that RACGAP1 was highly expressed in liver cancer tissues.Meanwhile,the expression of RACGAP1 in patients with liver cancer in the TCGA tumor database was further analyzed with the matching clinical data parameters.The expression level of RACGAP1 was significantly correlated with the pathological grade and T stage of liver cancer patients(all P<0.05),but was not significantly correlated with American Joint Committee on Cancer(AJCC)pathological stage and gender(P>0.05).There was a significant correlation between RACGAP1 expression level and overall survival(OS)in patients with liver cancer(P<0.05),and the overall survival time of patients with low expression was better than that of patients with high expression(P<0.05).Cox regression was used to analyze the correlation between T stage,M stage,N stage and RACGAP1 expression in patients with hepatocellular carcinoma(HCC),and RACGAP1 became an independent prognostic factor in patients with HCC(P<0.05).Conclusion:Based on the tumor-related gene information in the public database TCGA,RACGAP1 gene is highly expressed in liver cancer tissues and becomes an independent prognostic factor of liver cancer,which is expected to become an important therapeutic target of drug therapy for liver cancer.
基金supported by grants from the China Postdoctoral Science Foundation(Grant No.2022M712387)。
文摘Objective:To assess the clinical outcomes and toxicities of once daily(QD)simultaneous dose reduction intensity-modulated radiotherapy(SDR-IMRT-QD;SDR-QD)versus conventional QD IMRT(C-QD)and twice daily(BID)IMRT in patients with limited-stage small cell lung cancer(LS-SCLC).Methods:After propensity score matching(PSM),a retrospective analysis involving 300 patients with LS-SCLC treated using SDR-QD,C-QD,or BID was performed from January 1,2014 to December 31,2019.The prescribed irradiation dose in the SDR-QD cohort was 60 Gy/PGTV and 54 Gy/PTV QD.The radiation dose was 60 Gy for both PGTV and PTV QD in the C-QD cohort.The radiation dose was 45 Gy for both PGTV and PTV in the BID cohort.Toxicities,short-term effects,and survival outcomes were recorded.A meta-analysis on the protective effects of pharmaceuticals for cardiac toxicities induced by anti-tumor therapy was performed.Results:The median overall survival time(MST)in the 3 cohorts were 32.7 months(SDR-QD),26.3 months(C-QD),and 33.6 months(BID);the differences between groups were statistically significant.Lower toxicities and doses to organs-at-risk(OARs)occurred in the SDR-QD and BID cohorts.Further,the cardiac dose dosimetric parameter Vheart40 was negatively associated with survival(r=-0.35,P=0.007).A Vheart40 value of 16.5%was recommended as a cut-off point,which yielded 54.7%sensitivity and 85.7%specificity for predicting negative survival outcomes.The meta-analysis indicated that pharmaceuticals significantly reduced the cardiac toxicities induced by chemotherapy,but not radiotherapy.Conclusions:SDR-QD was shown to have similar toxicities and survival compared with BID,but fewer toxicities and better survival than C-QD.In addition,cardiac dose exposure was negatively associated with survival.Thus,16.5%of the cardiac dosimetric parameter Vheart40 is recommended as the cut-off point,and a Vheart40>16.5%predicts poor survival.
基金supported by the National Key R&D Program of China(Grant No.2018YFC1313400)。
文摘Exhausted T cells are a group of dysfunctional T cells,which are present in chronic infections or tumors.The most significant characteristics of exhausted T cells are attenuated effector cytotoxicity,reduced cytokine production,and upregulation of multiple inhibitory molecular receptors(e.g.,PD-1,TIM-3,and LAG-3).The intracellular metabolic changes,altered expression of transcription factors,and a unique epigenetic landscape constitute the exhaustion program.Recently,researchers have made progress in understanding exhausted T cells,with the definition and identification of exhausted T cells changing from phenotypebased to being classified at the transcriptional and epigenetic levels.Recent studies have revealed that exhausted T cells can be separated into two subgroups,namely TCF1^(+)PD-1^(+)progenitor-like precursor exhausted cells and TCF1-PD-1^(+)terminally differentiated exhausted T cells.Moreover,the progenitor-like precursor cell population may be a subset of T cells that can respond to immunotherapy.Studies have also found that TOX initiates and dominates the development of exhausted T cells at the transcriptional and epigenetic levels.TOX also maintains T cell survival and may affect decisions regarding treatment strategies.In this review,we discuss the latest developments in T cell exhaustion in regards to definitions,subpopulations,development mechanisms,differences in diverse diseases,and treatment prospects for exhausted T cells.Furthermore,we hypothesize that the epigenetic state regulated by TOX might be the key point,which can determine the reversibility of exhaustion and the efficacy of immunotherapy.
基金This work was supported by grants from the National Key R&D Program of China(Grant No.2018YFC1313400)the National Major Scientific and Technological Special Project for“Significant New Drug Development”of China(Grant No.2018ZX09201-015)the National Natural Science Foundation of China(Grants Nos.81872487,81872166,U20A20375,and 81974416).
文摘Objective:Distinguishing immune-related adverse events(irAEs)caused by immune checkpoint inhibitors(ICIs)from the AEs caused by chemotherapy,targeted therapy,or infection is highly difficult.This study offers new insights into evaluating the diagnosis,differential diagnostic,and prognostic value of ferritin for irAEs induced by ICIs.Methods:From December 1,2018,to April 1,2019,we examined 318 patients with malignant tumors who received serum ferritin monitoring.The cohort comprised 231 patients treated with PD-1 inhibitor or combination with chemotherapy,and 87 patients treated with chemotherapy.Of the 231 patients,90 had irAEs(irAE group),70 had non-irAEs(non-irAE group),67 had no AEs(no irAE-non irAE group),and 4 had unclassified AEs.In the 87 patients,60 had AEs(AE group),and 27 had no AEs(no AE group).Statistical analyses were conducted with nonparametric Mann-Whitney tests.Results:At the onset of AEs in the irAE group,ferritin(normal range,35–150μg/L)rose to a median of 927μg/L(range,117–17,825μg/L)from 86μg/L at baseline(range,29–421μg/L)(P<0.001).Ferritin levels at the onset of AEs in the irAE group were significantly higher than those in the non-irAE group(median,81μg/L;range,32–478μg/L)(P<0.001)and the AE group(median,103μg/L;range,23–712μg/L)(P<0.001).After treatment in the irAE group,ferritin continuously decreased to a normal range in recovered patients,showed no significant changes in stable patients,and continued to rise in patients who died.Conclusions:Ferritin can be used as a diagnostic,differential diagnostic,and prognostic marker for irAEs in patients treated with ICIs.
基金This study was supported by grants from the National Key R&D Program of China(Grant No.2018YFC1313400)the National Natural Science Foundation of China(Grant No.U20A20375).
文摘Tertiary lymphoid structures(TLSs)are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions,including infection,autoimmune disease,and cancer.In the tumor microenvironment(TME),the structures of TLSs,including B-cell-and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against cancers.Numerous studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer patients.It was shown that welldeveloped TLSs characterized by mature B cells synthesized tumor specific antibodies,which were considered as specific markers for a good prognosis.However,there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor responses.These factors include dysfunctional B cells,regulatory T cells,and T follicular regulatory cells.The complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs;it is therefore essential to fully understand the function and influencing factors in TLSs.It has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer immunotherapies.In this review,we focused on recent advances in TLSs in human solid tumors,including structural characteristics and classes,antitumor mechanisms,immunosuppressive factors,and TLSbased therapeutic approaches.
基金supported by National Basic Research Program of China (Grant No.2015CB964903)Natural Science Foundation of Tianjin (Grant No.15JCQNJC44800 and 18JCQNJC81300)+3 种基金National Natural Science Foundation of China (Grant No.81702481, 81701224, 81802873 and 81600083)CAMS Innovation Fund for Medical Sciences (Grant No.201612M-1-003 2017-12M-1-015)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (Grant No.2017PT31033, 2018RC31002, 2018PT32034)
文摘Objective: More than half of human glioblastomas show EGFR gene amplification and mutation, but EGFR inhibitors have not been effective in treating EGFR-positive glioblastoma patients.The mechanism behind this type of primary resistance is not well understood.The aim of this study was to investigate gefitinib resistance in glioblastoma, and explore ways to circumvent this significant clinical problem.Methods: MTT method was used to test the cell viability after EGFR-positive glioblastoma cells were treated with indicated drugs;real-time quantitative PCR method was included to detect the TNFα mRNA levels in glioma tissues and cell lines.ELISA was introduced to measure the TNFα protein levels in cell culture supernatant of glioblastoma cells treated with gefitinib.Western blot was used to detect the activity change of intracellular kinases in drug-treated glioblastoma cells.Two mouse xenograft tumor models were carried out to evaluate the in vivo effects of a combination of EGFR and TNFα inhibitors.Results: We found that glioblastoma resistance to gefitinib may be mediated by an adaptive pro-survival TNFα-JNK-Axl signaling axis, and that high TNFα levels in the glioblastoma microenvironment may further intensify primary resistance.A combination of the TNFα-specific small-molecule inhibitor C87 and gefitinib significantly enhanced the sensitivity of glioblastoma cells to gefitinib in vitro and in vivo.Conclusions: Our findings provide a possible explanation for the primary resistance of glioblastoma to EGFR inhibitors and suggest that dual blockade of TNFα and EGFR may be a viable therapeutic strategy for the treatment of patients with chemotherapy-refractory advanced glioblastoma.
基金This work was supported by grants from the National Key Technology R&D Program(Grant No.2018YFC1313400)National Natural Science Foundation of China(Grant No.81974246)+1 种基金Scientific Research Program of Tianjin Education Commission(Grant No.2019KJ185)Tianjin Research Innovation Project(Grant No.2020YJSB164)for postgraduate students.
文摘Objective:Lung cancer is the most common cause of cancer-related deaths worldwide.Somatic copy number alterations(SCNAs)have been used to predict responses to therapies in many cancers,including lung cancer.However,little is known about whether they are predictive of radiotherapy outcomes.We aimed to understand the prognostic value and biological functions of SCNAs.Methods:We analyzed the correlation between SCNAs and clinical outcomes in The Cancer Genome Atlas data for 486 patients with non-small cell lung cancer who received radiotherapy.Gene set enrichment analyses were performed to investigate the potential mechanisms underlying the roles of SCNAs in the radiotherapy response.Our results were validated in 20 patients with lung adenocarcinoma(LUAD)receiving radiotherapy.Results:SCNAs were a better predictor of progression-free survival(PFS)in LUAD(P=0.024)than in lung squamous carcinoma(P=0.18)in patients treated with radiotherapy.Univariate and multivariate regression analyses revealed the superiority of SCNAs in predicting PFS in patients with LUAD.Patients with stage I cancer and low SCNA levels had longer PFS than those with high SCNA levels(P=0.022).Our prognostic nomogram also showed that combining SCNAs and tumor/node/metastasis provided a better model for predicting long-term PFS.Additionally,high SCNA may activate the cell cycle pathway and induce tumorigenesis.Conclusions:SCNAs may be used to predict PFS in patients with early-stage LUAD with radiotherapy,in combination with TNM,with the aim of predicting long-term PFS.Therefore,SCNAs are a novel predictive biomarker for radiotherapy in patients with LUAD.
基金This work was supported by grants from The National Key R&D Program(Grant Nos.2018YFC1313400,2018YFC1313000,and 2018YFC1313002)The National Natural Science Foundation of China(Grant Nos.81872166,U20A20375,31600705,81974416,and 81702405)The Tianjin Natural Science Foundation(Grant No.17JCQNJC09000)。
文摘Objective:Trained immunity of natural killer(NK)cells has shown great potential in the treatment of cancers by eliciting enhanced effector responses to restimulation by cytokines or cancer cells for long time periods after preactivation.However,the human NK cells responsible for the generation and maintenance of trained immunity are largely unknown.We hypothesized that heterogeneous human NK cells would respond differentially to stimulation with a combination of IL-12,IL-15,and IL-18,and that an NK cell subset might exist that is mainly responsible for the induction of trained immunity.On the basis of our hypothesis,we aimed to identify the subset from which cytokine-trained human NK cells originate and to explore possible regulatory targets for drug intervention.Methods:Flow cytometry assays were performed to analyze the functions of cytokine-trained NK cells and examine cell division and protein expression in NK cell subsets.Single-cell RNA sequencing(scRNA-seq)plus TotalSeq™technology was used to track the heterogeneity of NK cells during the induction of trained immunity.Results:Traditional developmental markers for peripheral NK cells were unable to identify the precursors of human NK cells with trained immunity.Therefore,we used scRNA-seq plus TotalSeq™technology to track the heterogeneity of NK cells during the induction of trained immunity and identified a unique cluster of CD57−NKG2A+EZH2+IFNG+MKI67+IL12R+IL15R+IL18R+NK cells.Enrichment and pseudotime trajectory analyses suggested that this cluster of NK cells contained the precursor of trained NK cells.We then used flow cytometry to further investigate the role of EZH2 in trained NK precursors and found that CD57−NKG2A+EZH2+NK cells had faster cell cycles and an enhanced trained phenotype,and EZH2 inhibition significantly impaired the induction of trained immunity in NK cells.These results suggested that EZH2 is a unique epigenetic marker of precursors of human NK cells with trained immunity.Conclusions:Our work revealed human NK heterogeneity in the induction of trained immunity,identified the precursor subset for trained NK cells,and demonstrated the critical role of EZH2 in the induction of trained immunity in human NK cells.
基金supported by the National Key Technologies R&D Program of China grant Awards No.2015BAI12B12(to X.R.)and 2018YFC1313400(to J.X.)the National Natural Science Foundation of China grants Awards No.81572913 and 81872487(to L.L.).
文摘Dear Editor,Cytokine-induced killer(CIK)cells have been recognized as a new type of anti-tumor effector cells.CIK cells are a mixture of T lymphocytes.Among them,CD3+/CD56+T cells,which are rare in uncultured peripheral blood,are the main effector cells.CIK cells can proliferate rapidly in vitro,with stronger antitumor activity,broader target tumor spectrum,and lower adverse effect than other reported antitumor effector cells.1 Their ease of production in vitro and antitumor potential have made them suitable candidates for cell therapy regimens in solid and hematopoietic tumor treatments.1,2 Our previous retrospective study showed that the median progression-free survival(PFS)and overall survival(OS)in untreated,advanced non-small-cell lung cancer(NSCLC)patients who received CIK cell immunotherapy plus chemotherapy(13 and 24 months,respectively)were significantly longer than in those who received chemotherapy alone(6 and 10 months,respectively).2 But so far,there is no prospective,multicenter clinical study in lung cancer.Based on our previous study,we designed this randomized,multicenter,open-label trial to further evaluate the clinical efficacy of CIK cell immunotherapy plus chemotherapy in patients with advanced squamous NSCLC(ClinicalTrials.gov number,NCT01631357).