Prognostic value of circulating tumor cells combined with neutrophil-lymphocyte ratio in patients with hepatocellular carcinoma

BACKGROUND Circulating tumor cell(CTC)count and neutrophil-to-lymphocyte ratio(NLR)are both closely associated with the prognosis of hepatocellular carcinoma(HCC).AIM To investigate the prognostic value of combining these two indicators in HCC.METHODS Clinical data were collected from patients with advanced HCC who received im-mune therapy combined with targeted therapy at the Department of Oncology,the Affiliated Hospital of Southwest Medical University,Sichuan,China,from 2021 to 2023.The optimal cutoff values for CTC programmed death-ligand 1(PD-L1)(+)>1 or CTC PD-L1(+)≤1 and NLR>3.89 or NLR≤3.89 were evaluated using X-Tile software.Patients were categorized into three groups based on CTC PD-L1(+)counts and NLR:CTC-NLR(0),CTC-NLR(1),and CTC-NLR(2).The relationship between CTC-NLR and clinical variables as well as survival rates was assessed.RESULTS Patients with high CTC PD-L1(+)expression or NLR at baseline had shorter median progression-free survival(m-PFS)and median overall survival(mOS)than those with low levels of CTC PD-L1(+)or NLR(P<0.001).Mean-while,patients in the CTC-NLR(2)group showed a significant decrease in mPFS and mOS.Cox regression analysis revealed that alpha-fetoprotein(AFP),CTC PD-L1(+),and CTC-NLR were independent predictors of OS.The time-dependent receiver operating characteristic curve showed that the area under the curve of CTC-NLR at 12 months(0.821)and 18 months(0.821)was superior to that of AFP and CTC PD-L1(+).CONCLUSION HCC patients with high CTC PD-L1(+)or NLR expression tend to exhibit poor prognosis,and a high baseline CTC-NLR score may indicate low survival.CTC-NLR may serve as an effective prognostic indicator for patients with advanced HCC receiving immunotherapy combined with targeted therapy.

Nanomaterials for refining tumor microenvironment and enhancing therapy in head and neck squamous cell carcinoma: a review

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenuefor the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug deliverycarriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. Thisreview begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively exploredthe application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with usingNMs in biomedical research.

Circulating tumor cells as prognostic marker in pancreatic cancer

In this editorial we comment on the article by Zhang et al published in the recent issue of the World Journal of Clinical Oncology.Pancreatic cancer is the fourth most common cause of cancer-related mortality and has the lowest survival rate among all solid cancers.It causes 227000 deaths annually worldwide,and the 5-year survival rate is very low due to early metastasis,which is 4.6%.Cancer survival increases with better knowledge of risk factors and early and accurate diagnosis.Circulating tumor cells(CTCs)are tumor cells that intravasate from the primary tumor or metastasis foci into the peripheral blood circulation system spontan-eously or during surgical operations.Detection of CTC in blood is promising for early diagnosis.In addition,studies have associated high CTC levels with a more advanced stage,and more intensive treatments should be considered in cases with high CTC.In tumors that are considered radiologically resectable,it may be of critical importance in detecting occult metastases and preventing unnecessary surgeries.

Thoracic giant cell tumor after two total en bloc spondylectomies including one emergency surgery:A case report

BACKGROUND For patients with acute paraplegia caused by spinal giant cell tumor(GCT)who require emergency decompressive surgery,there is still a lack of relevant reports on surgical options.This study is the first to present the case of an acute paraplegic patient with a thoracic spinal GCT who underwent an emergency total en bloc spondylectomy(TES).Despite tumor recurrence,three-level TES was repeated after denosumab therapy.CASE SUMMARY A 27-year-old female patient who underwent single-level TES in an emergency presented with sudden severe back pain and acute paraplegia due to a thoracic spinal tumor.After emergency TES,the patient's spinal cord function recovered,and permanent paralysis was avoided.The postoperative histopathological examination revealed that the excised neoplasm was a rare GCT.Unfortunately,the tumor recurred 9 months after the first surgery.After 12 months of denosumab therapy,the tumor size was reduced,and tumor calcification.To prevent recurrent tumor progression and provide a possible cure,a three-level TES was performed again.The patient returned to an active lifestyle 1 month after the second surgery,and no recurrence of GCT was found at the last follow-up.CONCLUSION This patient with acute paraplegia underwent TES twice,including once in an emergency,and achieved good therapeutic results.TES in emergency surgery is feasible and safe when conditions permit;however,it may increase the risk of tumor recurrence.

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

Do Tumor Characteristics and Pre-Transplant Locoregional Therapy Predict Survival after OLT in Patients with Hepatocellular Carcinoma?

HCC prognosis after OLT is associated with criteria related to the number and size. However, the degree of differentiation and efficacy of locoregional therapies may also influence outcome. Aim: Characterize patients with and without HCC and compare outcomes according to tumor characteristics. Methods: Retrospective query of an electronic medical record of 328 patients transplanted at California Pacific Medical Center (CPMC) in 2001-2007. HCC was defined by pre-OLT listing data as well as the finding of a tumor consistent with HCC at liver explant. Milan and UCSF criteria were applied to the lesions as described by pathology upon explant examination. Results: 328 patients were evaluated, with 109 liver malignancies, 103 females (26 (25%) HCC) and 225 males (83 (37%) HCC p = 0.04). HCC patients were older (56 ± 7.2 yr) than non HCC patients (51 ± 9.2, p 0.001). The age of the donor and cold ischemia time was not different in the 2 groups. Survival was shorter in HCC (mean 984 ± 599 days) vs. non HCC (1103 ± 642) but not statistically significant (p = 0.10). Kaplan Meier survivals were superposable when comparing patients with or without malignancy and when patients with low (≤22) vs. high MELD (>22) were compared. Survival curves in patients that fulfilled Milan vs. UCSF criteria were identical. However, more patients outside Milan died of metastatic disease (5/6, 83%) vs. within Milan (6/14, 43%, p = 0.01). Cox proportional hazards regression showed that MELD, but not malignancy, differentiation or necrosis, was associated with mortality;HR = 6% (95% C.I. 1%-10%) per additional MELD point (p = 0.02). 69 pts had TACE pre-OLT, 17 had RFA ± any other modality. There was no difference in survivals in pts who received any locoregional therapy vs. those who did not (p

Clinical implications and perspectives of portal venous circulating tumor cells in pancreatic cancer

Despite recent improvements in the diagnosis and treatment of pancreatic cancer(PC),clinical outcomes remain dismal.Moreover,there are no effective prognostic or predictive biomarkers or options beyond carbohydrate antigen 19-9 for personalized and precise treatment.Circulating tumor cells(CTCs),as a member of the liquid biopsy family,could be a promising biomarker;however,the rarity of CTCs in peripheral venous blood limits their clinical use.Because the first venous drainage of PC is portal circulation,the portal vein can be a more suitable location for the detection of CTCs.Endoscopic ultrasound-guided portal venous sampling of CTCs is both feasible and safe.Several studies have suggested that the detection rate and number of CTCs may be higher in the portal blood than in the peripheral blood.CTC counts in the portal blood are highly associated with hepatic metastasis,recurrence after surgery,and survival.The phenotypic and genotypic properties measured in the captured portal CTCs can help us to understand tumor heterogeneity and predict the prognosis of PC.Small sample sizes and heterogeneous CTC detection methods limit the studies to date.Therefore,a large number of prospective studies are needed to corroborate portal CTCs as a valid biomarker in PC.

Research Status of CAR-T Cell Immunotherapy in Tumor Treatment

In recent years, chimeric antigen receptor T-cell (CAR-T) therapy has made breakthroughs in the treatment of hematological tumors. However, due to the different characteristics of solid tumors from hematological tumors, CAR-T has not achieved good efficacy in the treatment of solid tumors. The key factors limiting the efficacy of CAR-T mainly include the solid tumor cells themselves and their special tumor microenvironment (TME), which damage CAR-T function in multiple processes such as CAR-T infiltration to tumor tissue sites, CAR-T maintaining anti-tumor activity in TME, and target recognition and killing of tumor cells by CAR-T. To solve these problems, more and more preclinical studies have proposed potentially effective solutions, and corresponding clinical studies have been carried out one after another. In this article, the existing challenges and corresponding optimization strategies of CAR-T cell therapy for solid tumors will be reviewed, to provide a reference for the future exploration of CAR-T therapy.

Evaluation of epithelial-mesenchymal transitioned circulating tumor cells in patients with resectable gastric cancer: Relevance to therapy response

AIM: To evaluate the epithelial-to-mesenchymal transition(EMT) of circulating tumor cells(CTCs) in gastric cancer patients.METHODS: We detected tumor cells for expression of four epithelial(E^+) transcripts(keratins 8, 18, and 19 and epithelial cell adhesion molecule) and two mesenchymal(M^+) transcripts(Vimentin and Twist) by a quantifiable, dual-colorimetric RNA-in situ hybridization assay. Between July 2014 and October 2014, 44 patients with gastric cancer were recruited for CTC evaluation. Blood samples were obtained from selected patients during the treatment course [before surgery, after surgery and at the 6^(th) cycle of XELOX based chemotherapy(about 6 mo postoperatively)].RESULTS: We found the EMT phenomenon in which there were a few biphenotypic E^+/M^+ cells in primary human gastric cancer specimens. Of the 44 patients, the presence of CTCs was reported in 35(79.5%) patients at baseline. Five types of cells including from exclusively E^+ CTCs to intermediate CTCs and exclusively M^+ CTCs were identified(4 patients with M^+ CTCs and 10 patients with M^+ or M^+ > E^+ CTCs). Further, a chemotherapy patient having progressive disease showed a proportional increase of mesenchymal CTCs in the post-treatment blood specimens. We used NCI-N87 cells to analyze the linearity and sensitivity of Can Patrol^(TM) system and the correlation coefficient(R^2) was 0.999.CONCLUSION: The findings suggest that the EMT phenomenon was both in a few cells of primary tumors and abundantly in CTCs from the blood of gastric cancer patients, which might be used to monitor therapy response.

Reduction of tumorigenicity of SMMC-7721 hepatoma cells by vascular endothelial growth factor antisense gene therapy

AIM: To test the hypothesis to block VEGF expression of SMMC-7721 hepatoma cells may inhibit tumor growth using the rat hepatoma model. METHODS: Amplify the 200 VEGF cDNA fragment and insert it into human U6 gene cassette in the reverse orientation transcribing small antisense RNA which could specifically interact with VEGF165, and VEGF121 mRNA. Construct the retroviral vector containing this antisense VEGF U6 cassette and package the replication-deficient recombinant retrovirus. SMMC-7721 cells were transduced with these virus and positive clones were selected with G418. PCR and Southern blot analysis were performed to determine if U6 cassette integrated into the genomic DNA of positive clone. Transfected tumor cells were evaluated for RNA expression by ribonuclease protection assays. The VEGF protein in the supernatant of parental tumor cells and genetically modified tumor cells was determined with ELISA. In vitro and in vivo growth properties of antisense VEGF cell clone in nude mice were analyzed. RESULTS: Restriction enzyme digestion and PCR sequencing verified that the antisense VEGF RNA retroviral vector was successfully constructed.After G418 selection, resistant SMMC-7721 cell clone was picked up. PCR and Southern blot analysis suggested that U6 cassette was integrated into the cell genomic DNA. Stable SMMC-7721 cell clone transduced with U6 antisense RNA cassette could express 200 bp small antisense VEGF RNA and secrete reduced levels of VEGF in culture condition. Production of VEGF by antisense transgene-expressing cells was 65+/-10 ng/L per 10(6) cells, 42045 ng/L per 10(6) cells in sense group and 485+/-30 ng/L per 10(6) cells in the negative control group, (P【 0.05). The antisense-VEGF cell clone appeared phenotypically indistinguishable from SMMC-7721 cells and SMMC-7721 cells transfected sense VEGF. The growth rate of the antisense-VEGF cell clone was the same as the control cells. When S.C. was implanted into nude mice, growth of antisense-VEGF cell lines was greatly inhibited compared with control cells. CONCLUSION: Expression of antisense VEGF RNA in SMMC-7721 cells could decrease the tumorigenicity, and antisense-VEGF gene therapy may be an adjuvant treatment for hepatoma.

Association between genetic variations in tumor necrosis factor receptor genes and survival of patients with T-cell lymphoma

The prognosis of T-cell lymphoma (TCL) has been shown to be associated with the clinical characteristics of patients. However, there is little knowledge of whether genetic variations also affect the prognosis of TCL. This study investigated the associations between single nucleotide polymorphisms(SNPs) in tumor necrosis factor receptor superfamily(TNFRSF) genes and the survival of patients with TCL. A total of 38 tag SNPs in 18 TNFRSF genes were genotyped using Sequenom platform in 150 patients with TCL. Kaplan-Meier survival estimates were plotted and significance was assessed using log-rank tests. Cox proportional hazard models were used to analyze each of these 38 SNPs with adjustment for covariates that might influence patient survival, including sex and international prognostic Index score. Hazard ratios (HRs) and their 95% confidence intervals(CIs) were calculated. Among the 38 SNPs tested, 3 were significantly associated with the survival of patients with TCL. These SNPs were located at LTβR (rs3759333C>T) and TNFRSF17(rs2017662C>T and rs2071336C>T). The 5-year survival rates were significantly different among patients carrying different genotypes and the HRs for death between the different genotypes ranged from 0.45 to 2.46. These findings suggest that the SNPs in TNFRSF genes might be important determinants for the survival of TCL patients.

Shear Stress Regulates Tumor Cell Mechanics and Actomyosin-Dependent Survival and Chemoresistance

Metastasis is the main cause of cancer death,and tumor cells mainly disseminate to the distal organs through the blood circulation,in which they experience considerable levels of fluid shear stress.CTCs are heterogeneous with diverse subpopulations of distinct genotypes and phenotypes and the frequency of CTCs is correlated with poor prognosis and overall survival in cancer patients.Less than 0.01%of them may eventually generate metastatic tumors in secondary sites,indicating the inefficiency of metastasis.Nevertheless,metastasis accounts for over 90%of cancer-related deaths,suggesting that a subpopulation of CTCs are able to survive the metastatic process and form metastases.To target metastasis,it is thus essential to understand the roles of various factors during dissemination in the survival and functions of CTCs.However,the effects of hemodynamic shear stress on biophysical properties and functions of CTCs in suspension are not fully understood.This study was to investigate the effect of hemodynamic shear stress on the survival and anti-chemotherapy ability of suspended circulating tumor cells during metastasis,and the effect of actomyosin activity on this regulation.In this study,we developed a circulatory system to generate physiologic levels of hemodynamic shear stress,which mimicked certain important aspects of the CTC microenvironment in blood circulation.The survival of tumor cells in suspension,as a model for real CTCs,under different shear stress and circulation duration was examined.We found that the majority of breast tumor cells s in suspension can be eliminated by hemodynamic shear stress.The surviving cells exhibit unique biophysical properties,including significantly retarded cell adhesion,mesenchymal-like cell morphology,and reduced F-actin expression and cellular stiffness.Cancer stem cells which has been reported in other papers have lower stiffness compared with conventional tumor cells showed significantly higher survival in blood flow.Importantly,low actomyosin activity promotes the survival of CTCs in blood shear flow while high actomyosin activity inhibits tumor cells surviving shear stress treatment.These findings might be explained by the up-and down-regulation of the anti-apoptosis genes.Soft surviving tumor cells held survival advantages in shear flow and higher resistance to chemotherapy.Metastasis is closely linked with chemoresistance.However,the underlying mechanisms have not been fully understood,in particular,the roles of hemodynamic shear stress and actomyosin-dependent cell mechanics in drug resistance of CTCs remain unclear.Inhibiting actomyosin activity in suspended tumor cells enhanced chemoresistance,while activating actomyosin suppressed this ability.These findings might be associated with the corresponding changes in multidrug resistance related genes.Our study unveils the regulatory roles of actomyosin in the survival and drug resistance of circulating tumor cells in hemodynamic shear flow,which imply the importance of fluid shear stress and actomyosin activity in tumor metastasis.Our findings reveal a new mechanism by which circulating tumor cells are able to survive hemodynamic shear stress and chemotherapy and may offer a new potential strategy to target circulating tumor cells in shear flow and combat chemoresistance through actomyosin.

Assessment of Prognostic Factors of Racial Disparities in Testicular Germ Cell Tumor Survival in the United States(1992–2015)

Objective Testicular germ cell tumors(TGCT) are the most common cancer among men aged 15 to 39 years. Previous studies have considered factors related to TGCT survival rate and race/ethnicity, but histological type of the diagnosed cancer has not yet been thoroughly assessed.Methods The data came from 42,854 eligible patients from 1992 to 2015 in the Surveillance Epidemiology and End Results 18. Frequencies and column percent by seminoma and nonseminoma subtypes were determined for each covariates. We used Cox proportional hazard regression to assess the impact of multiple factors on post-diagnostic mortality of TGCT.Results Black males were diagnosed at a later stage, more commonly with local or distant metastases.The incidence of TGCT in black non-seminoma tumors increased most significantly. The difference in survival rates between different ethnic and histological subtypes, overall survival(OS) in patients with non-seminoma was significantly worse than in patients with seminoma. The most important quantitative predictor of death was the stage at the time of diagnosis, and older diagnostic age is also important factor affecting mortality.Conclusion Histological type of testicular germ cell tumor is an important factor in determining the prognosis of testicular cancer in males of different ethnic groups.

Nanotherapeutics approaches to improve the efficacy of CAR-T cells in solid tumors

Adoptive cell therapy and Immune Checkpoint Blockade Inhibitors have recently revolutionized the field of oncology.However,these types of immunotherapeutic approaches have limited success in treating solid tumors.In particular,chimeric antigen receptor(CAR)-T cells efficacy is hampered by immunosuppressive signals in the tumor microenvironment(TME)and by a limited infiltration of re-infused T cells to the tumor site.The field of nanobiotechnology applied to oncology is also rapidly expanding.Nanoparticles-based delivery systems can be employed to modulate the activity of immune cells present in the TME enhancing the efficacy of CAR-T cells.Interestingly,nano-backpacks can be attached to CAR-T cells prior to re-infusion to support their homing to the tumor site and to slowly release immunopotentiators directly in the TME.Furthermore,nanovaccines can also be employed to support the in vivo expansion of CAR-T cells with consequent enhancement of their therapeutic potential.In this viewpoint,recent advancement in the field of nanobiotechnology to support CAR-T cell therapy will be discussed.The development of novel therapeutic CAR-T cells protocols together with nanotherapies is warranted in order to take full advantage of the high therapeutic potential of CAR-T cell therapy.

Discussion of rationality of radiosurgery therapy on pineal region germ cell tumors

Objective To discuss rationality of stereotaxic radiosurgery as the first therapy strategy on pineal region germ cell tumors. Methods To retrospectively analyze the clinical materials of 14cases which received the treatment of gamma knife or X-knife. The condition of tumor changing ,recurrence

Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

Severe immunosuppression is a hallmark of colorectal cancer(CRC).Myeloid-derived suppressor cells(MDSCs),one of the most abundant components of the tumor stroma,play an important role in the invasion,metastasis,and immune escape of CRC.MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells,including T and natural killer cells,as well as by inducing the proliferation of immunosuppressive cells,such as regulatory T cells and tumor-associated macrophages,which,in turn,promote the growth of cancer cells.Thus,MDSCs are key contributors to the emergence of an immunosup-pressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity.In this narrative review,we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment,the current therapeutic approaches and technologies targeting MDSCs,and the therapeutic potential of modulating MDSCs in CRC treatment.This study provides ideas and methods to enhance survival rates in patients with CRC.

Tumor neoantigens: Novel strategies for application of cancer immunotherapy

Neoantigen-targeted immunotherapy is a rapidly advancing field that holds great promise for treating cancer.The recognition of antigens by immune cells is a crucial step in tumor-specific killing,and neoantigens generated by mutations in cancer cells possess high immunogenicity and are selectively expressed in tumor cells,making them an attractive therapeutic target.Currently,neoantigens find utility in various domains,primarily in the realm of neoantigen vaccines such as DC vaccines,nucleic acid vaccines,and synthetic long peptide vaccines.Additionally,they hold promise in adoptive cell therapy,encompassing tumor-infiltrating cells,T cell receptors,and chimeric antigen receptors which are expressed by genetically modified T cells.In this review,we summarized recent progress in the clinical use of tumor vaccines and adoptive cell therapy targeting neoantigens,discussed the potential of neoantigen burden as an immune checkpoint in clinical settings.With the aid of state-of-the-art sequencing and bioinformatics technologies,together with significant advancements in artificial intelligence,we anticipated that neoantigens will be fully exploited for personalized tumor immunotherapy,from screening to clinical application.

Immune modulations of the tumor microenvironment in response to phototherapy

The tumor microenvironment(TME)promotes pro-tumor and anti-infammatory metabolismsand suppresses the host immune system.It prevents immune cells from fighting against cancereffectively,resulting in limited efficacy of many current cancer treatment modalities.Differenttherapies aim to overcome the immunosuppressive TME by combining various approaches tosynergize their effects for enhanced antitumor activity and augmented stimulation of the im-mune system.Immunotherapy has become a major therapeutic strategy because it unleashes thepower of the immune system by activating,enhancing,and directing immune responses to pre-vent,control,and eliminate cancer.Phototherapy uses light iradiation to induce tumor celldeath through photothermal,photochemical,and photo-immunological interactions.Photo-therapy induces tumor immunogenic cell death,which is a precursor and enhancer for anti-tumorimmunity.However,phototherapy alone has limited effects on long-term and systemic anti-tumor immune responses.Phototherapy can be combined with immunotherapy to improve thetumoricidal effect by killing target tumor cells,enhancing immune cell infiltration in tumors,andrewiring pathways in the TME from antinfammatory to pro-inflammatory.Phototherapy-enhanced immunotherapy triggers effective cooperation bet ween innate and adaptive immunities,specifically targeting the tumor cells,whether they are localized or distant.Herein,the successes and limitations of phototherapy combined with other cancer treatmentmodalities will be discussed.Specifically,we will review the symergistic effects of phototherapy combined with different cancer therapies on tumor elimination and remodeling of the immuno-suppressive TME.Overll,phototherapy,in combination with other therapeutic modalities,canestablish anti-tumor pro-infammatory phenotypes in activated tumor-infiltrating T cells andB cells and activate systemic anti-tumor immune responses.

The clinical association of programmed cell death protein 4(PDCD4) with solid tumors and its prognostic significance:a meta-analysis

Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical signiicance and prognostic value of PDCD4 in solid tumors.Methods: A systematic literature review was performed to retrieve publications with available clinical informa?tion and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta?analysis Of Observational Studies in Epidemiology group. Pooled odds ratios(ORs), hazard ratios(HRs), and 95% conidence intervals(CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests.Results: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was signiicantly associated with the diferentiation status of head and neck cancer(OR 4.25, 95% CI 1.87–9.66) and digestive system cancer(OR 2.87, 95% CI 1.84–4.48). Down?regulation of PDCD4 was signiicantly associated with short overall survival of patients with head and neck(HR: 3.44, 95% CI 2.38–4.98), breast(HR: 1.86, 95% CI 1.36–2.54), digestive system(HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers(HR: 3.16, 95% CI 1.06–9.41).Conclusions: The current evidence suggests that PDCD4 down?regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be conirmed by large?scale prospective studies.

Endostatin enhances antitumor effect of tumor antigen-pulsed dendritic cell therapy in mouse xenograft model of lung carcinoma

Objective： To investigate the antitumor effect of endostatin combined with tumor antigen-pulsed dendritic cell （DC）-T cell therapy on lung cancer. Methods： Transplanted Lewis lung cancer （LLC） models of C57BL/6 mice were established by subcutaneous injection of LLC cells in left extremity axillary. Tumor antigen-pulsed DC-T cells from spleen cells and bone of mice were cultured in vitro. Tumor-bearing mice were randomly divided into three groups, including DC- T＋endostatin group, DC-T group, and phosphate-buffered saline （PBS） control group. Microvessel density （MVD） of tumor tissue in tumor-bearing mice was determined by immunohistochemistry （IHC）. The expressions of vascular endothelial growth factor （VEGF） and hypoxia-inducible factor-1α （HIF-1α） were determined by Western blotting and IHC staining. The proportions of CD8＋ T cells, mature dendritic cells （mDC）, tumor-associated macrophages [TAM （M1/M2）], and myeloid-derived suppressor cells （MDSC） in suspended cells of tumor tissue were determined by flow cytometry. The expressions of inter｜eukin （IL）-6, IL-10, IL-17, transforming growth factor-β（TGF-β） and interferon-γ （IFN-γ） in suspended cells of tumor tissue were detected by enzyme-linked immune sorbent assay （ELISA）. Results： DC-T cells combined with endostatin remarkably suppressed tumor growth. MVD of mice in DC- T＋endostatin group was significantly lower than that of the control group and DC-T monotherapy group. The expressions of VEGF, IL-6 and IL-17 in tumors were markedly decreased, but IFN-γ, and HIF-1α increased after treating with DC-T cells combined with endostatin, compared to control group and DC-T group. In the DC- T＋endostatin group, the proportions of MDSC and TAM （M2 type） were significantly decreased, mDC and TAM （Nil type） were up-regulated, and CD8＋ T cells were recruited to infiltrate tumors, in contrast to PBS control and DC-T monotherapy. DC-T cells combined with endostatin potently reduced the expressions of IL-6, IL-10, TGF-β and IL-17 in tumor tissue, and enhanced the expression of IFN-γ. Conclusions： The study indicated the synergic antitumor effects between endostatin and tumor antigen-pulsed DC-T cells, which may be a prospective therapy strategy to achieve potent antitumor effects on lung cancer.