Association of tumor budding with clinicopathological features and prognostic value in stage III-IV colorectal cancer

BACKGROUND Tumor budding(TB)has emerged as a promising independent prognostic biomarker in colorectal cancer(CRC).The prognostic role of TB has been extensively studied and currently affects clinical decision making in patients with stage I and II CRC.However,existing prognostic studies on TB in stage III CRC have been confined to small retrospective cohort studies.Consequently,this study investigated the correlation among TB categories,clinicopathological features,and prognosis in stage III-IV CRC to further enhance the precision and individualization of treatment through refined prognostic risk stratification.AIM To analyze the relationship between TB categories and clinicopathological characteristics and assess their prognostic value in stage III-IV CRC to further refine the prognostic risk stratification of stage III-IV CRC.METHODS The clinical data of 547 CRC patients were collected for this retrospective study.Infiltration at the front edge of the tumor buds was counted according to the 2016 International Tumor Budding Consensus Conference guidelines.RESULTS Multivariate Cox proportional hazards regression analysis demonstrated that chemotherapy(P=0.004),clinical stage IV(P<0.001),≥4 regional lymph node metastases(P=0.004),left-sided colonic cancer(P=0.040),and Bd 2-3(P=0.002)were independent prognostic factors in patients with stage III-IV CRC.Moreover,the density of tumor infiltrating lymphocytes was higher in Bd 1 than in Bd 2-3,both in the tumor stroma and its invasive margin.CONCLUSION TB has an independent predictive prognostic value in patients with stage III-IV CRC.It is recommended to complete the TB report of stage III-IV CRC cases in the standardized pathological report to further refine risk stratification.

Immune signature of small bowel adenocarcinoma and the role of tumor microenvironment

In this editorial we comment on the article published“Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment”.Small bowel adenocarcinoma(SBA)is a rare gastrointestinal neoplasm and despite the small intestine's significant surface area,SBA accounts for less than 3%of such tumors.Early detection is challenging and the reason arises from its asymptomatic nature,often leading to late-stage discovery and poor prognosis.Treatment involves platinum-based chemotherapy with a 5-fluorouracil combination,but the lack of effective chemotherapy contributes to a generally poor prognosis.SBAs are linked to genetic disorders and risk factors,including chronic inflammatory conditions.The unique characteristics of the small bowel,such as rapid cell renewal and an active immune system,contributes to the rarity of these tumors as well as the high intratumoral infiltration of immune cells is associated with a favorable prognosis.Programmed cell death-ligand 1(PD-L1)expression varies across different cancers,with potential discrepancies in its prognostic value.Microsatellite instability(MSI)in SBA is associated with a high tumor mutational burden,affecting the prognosis and response to immunotherapy.The presence of PD-L1 and programmed cell death 1,along with tumor-infiltrating lymphocytes,plays a crucial role in the complex microenvironment of SBA and contributes to a more favorable prognosis,especially in the context of high MSI tumors.Stromal tumor-infiltrating lymphocytes are identified as independent prognostic indicators and the association between MSI status and a favorable prognosis,emphasizes the importance of evaluating the immune status of tumors for treatment decisions.

Tumor infiltrating lymphocytes in gastric cancer:Unraveling complex interactions for precision medicine

This editorial will focus on tumor immunity and the factors that alter the tumor immune micro-environment.The role of tumor infiltrating lymphocytes(TILs)will also be discussed in detail,including the types,mechanism of action,and role.Gastric cancer(GC)often presents in the advanced stage and has various factors predicting the outcomes.The interplay of these factors and their correlation with the TILs is discussed.A literature review revealed high intratumoral TILs associated with higher grade,HER2-,and Helicobacter pylori negativity.Moreover,stromal(ST)TILs correlated with lower grade and lesser recurrence risk in GC.High TILs in ST and invasive border also correlated with mismatch repair deficiency status.Further characterization of the CD3+,CD8+,and other cells is also warranted.In the future,this complex correlation of cancer cells with the immune system can be explored for therapeutic avenues.

IQGAP3 promotes the progression of glioma as an immune and prognostic marker

Background:IQGAP3 plays a crucial role in regulating cell proliferation,division,and cytoskeletal organization.Abnormal expression of IQGAP3 has been linked to various tumors,but its function in glioma is not well understood.Methods:Various methods,including genetic differential analysis,single-cell analysis,ROC curve analysis,Cox regression,Kaplan-Meier analysis,and enrichment analysis,were employed to analyze the expression patterns,diagnostic potential,prognostic implications,and biological processes involving IQGAP3 in normal and tumor tissues.The impact of IQGAP3 on immune infiltration and the immune microenvironment in gliomas was evaluated using immunofluorescence.Additionally,the cBioPortal database was used to analyze copy number variations and mutation sites of IQGAP3.Experimental validation was also performed to assess the effects of IQGAP3 on glioma cells and explore underlying mechanisms.Results:High IQGAP3 expression in gliomas is associated with an unfavorable prognosis,particularly in wild-type IDH and 1p/19q non-codeleted gliomas.Enrichment analysis revealed that IQGAP3 is involved in regulating the cell cycle,PI3K/AKT signaling,p53 signaling,and PLK1-related pathways.Furthermore,IQGAP3 expression may be closely related to the immunosuppressive microenvironment of glioblastoma.BRD-K88742110 and LY-303511 are potential drugs for targeting IQGAP3 in anti-glioma therapy.In vitro experiments showed that downregulation of IQGAP3 inhibits the proliferation and migration of glioma cells,with the PLK1/PI3K/AKT pathway potentially playing a crucial role in IQGAP3-mediated glioma progression.Conclusion:IQGAP3 shows promise as a valuable biomarker for diagnosis,prognosis,and immunotherapeutic strategies in gliomas.

Evaluating tumor-infiltrating lymphocytes in hepatocellular carcinoma using hematoxylin and eosin-stained tumor sections

BACKGROUND Tumor-infiltrating lymphocytes(TILs)constitute a prognostic factor in hepatocellular carcinoma(HCC).However,different methods of assessing TILs have various pre-analytical,analytical,and post-analytical challenges.The evaluation of TILs in hematoxylin and eosin(H&E)-stained tumor sections proposed by the International Immuno-Oncology Biomarker Working Group was demonstrated to be a reproducible,affordable and easily applied method in many tumors.AIM To evaluate the prognostic significance of TILs in H&E-stained slides of HCCs.METHODS This was a retrospective study performed in the hospital.HCC patients who underwent liver resection between 2015 and 2017 in Zhongshan Hospital were enrolled in this study.Patients who experienced recurrence or received therapy in addition to antiviral therapy before surgery at this time were excluded.A total of 204 patients were enrolled in the study.The ILs were counted manually in tumor sections stained with H&E under an optical microscope at 400×.The ILs were assessed separately in the center of the tumor(TILs^(CT)),the invasive front(TILs^(IF)),and peritumor(PILs)areas.Univariate and multivariate survival analyses were performed using a Cox regression model.P<0.05 was considered statistically significant and all P-values were two-sided.RESULTS Among the 204 patients,univariate analysis indicated that macrovascular invasion(MaVI)(P=0.001),microvascular invasion(MVI)(P=0.012),multiple tumors(P=0.008),large tumors(>10 cm)(P=0.001),absence of a tumor capsule(P=0.026),macrotrabecular histological subtype(P=0.001),low density of TILs^(CT)(P=0.039),TILs^(IF)(P=0.014),and PILs(P=0.010)were predictors of progressionfree survival(PFS).Cox multivariate analysis indicated that MaVI(P=0.009),absence of a tumor capsule(P=0.031),low-density of TILs^(IF)(P=0.047)and PILs(P=0.0495)were independent predictors of PFS.A three-category analysis was carried out by combining TILs^(CT),TILs^(IF),and PILs,after which HCCs were classified into immune^(high)[(TILs^(CT))^(high),(TILs^(IF))^(high),and PILs^(high),83 cases],immune^(mod)(tumors other than immune^(high) and immune^(low) subtypes,94 cases),and immune^(low)[(TILs^(CT))^(low),(TILs^(IF))^(low),and PILs^(low),27 cases]subtypes.The immune^(high) subtype had a lower rate of MVI(40.96%)than the immune^(mod)(61.70%,P=0.017)and immune^(low)(66.67%,P=0.020)subtypes.The recurrence rates of the immune^(high),immune^(mod) and immune^(low) subtypes were 10.8%,25.5%and 33.3%,respectively.CONCLUSION HCC patients with high infiltrating lymphocytes tend to have a lower recurrence rate and less MVI.The evaluation of TILs in H&E-stained specimens could be a prognostic parameter for HCC.

EXPRESSION AND SIGNIFICANCE OF TUMOR INFILTRATING DENDRITIC CELLS IN RENAL CELL CARCINOMA

Objective: To study the expression of dendritic cells in human renal cell carcinoma and explore the cause, so to reveal the mechanism of escaping immune surveillance in RCC. Methods: The expressions of CD83+DCS, CD1a+DCS,VEGF and TGF-β1 in tumoral, peritumoral and normal kidney tissues of RCC in 30 cases were detected by immunohistochemistry using streptavidin/peroxidese(SP) Results: CD83+DCS were mainly located in the peritumoral areas; whereas CD1a+DCS、were mainly retained within the cancer nests. The number of CD83+DCS was inversely correlated with the clinical stage(P<0.05); but there were no significant correlations between the number of CD1a+DCS、and the clinical stage(P>0.05). The expressions of CD83+DCS and CD1a+DCS have significant difference between the tumoral, peritumoral and normal kidney tissues(P<0.001). The expression of VEGF and TGF-β1 were significantly lower in samples with highly infiltrating CD83+DCS(P<0.05); Whereas CD1a+DCS were not (P>0.05). Conclusion: DC has the tendency to gathering in tumor, but because of the immunosuppressive cytokins, for example VEGF and TGF-β1, inhibits the maturation of DC, there are less mature TIDCS(CD83+TIDCS) in the tumoral tissues, they are mainly located in the peritumoral areas. This may contribute to the mechanism of escaping immune surveillance in RCC.

Effect of Tumor Infiltrating Lymphocyte on Local Control of Rectal Cancer after Preoperative Radiotherapy

Objective： To study the effect of tumor infiltrating lymphocytes at cancer nest on local control of rectal cancer after preoperative radiotherapy. Methods： From Jan. 1999 to Oct. 2007, a total of 107 patients with rectal cancer were reviewed. They were treated by preoperative radiotherapy, 30 Gy/10 fractions/12 days. Two weeks later, the patient underwent a surgical operation. Their pathological samples were kept in our hospital before and after radiotherapy. Lymphocyte infiltration （LI） degree, pathologic degradation and fibrosis degree after radiotherapy in paraffin section were evaluated under microscope. Results： After followed-up of 21 months （2-86 months）, a total of 107 patients were reviewed. Univariate analysis showed that lymphocyte infiltration （LI）, fibrosis and pathologic changes after radiotherapy were significant factors on local control. Logistic regression analysis showed that LI after radiotherapy was a significant effect factor on local control. Conclusion： LI, fibrosis and pathologic degradation after radiotherapy are significant for local control of rectal cancer after preoperative radiotherapy. LI after radiotherapy was a significantly prognostic index for local control of rectal cancer after preoperative radiotherapy.

PREPARATION AND CYTOLYTIC TUMOR ACTIVITY OF OSTEOSARCOMA TUMOR INFILTRATING LYMPHOCYTES IN VITRO

In this study, the isolation, purification and differentiation of tumor-lnflltratlng lymphocytes (TIL) from 6 fresh osteosarcoma specimens were achieved by discontinuous density gradient centrifugation. One specimen of the osteosarcoma TIL were enlarged in IL-2 for long time in vitro, reaching 28 days and their cytolytic activity against different tumor cell lines was Investigated. The experimental results indicated that the preparation of osteosarcoma TIL adopted by the mechanical means was simple, having higher purifity, keeping higher effects on killing NK- sensitive tumor cell lines and NK-insensitive tumor cell lines as well as rapid proliferation in vitro cultured in IL-2.

Histological differentiation impacts the tumor immune microenvironment in gastric carcinoma:Relation to the immune cycle

BACKGROUND Various histological types of gastric carcinomas(GCs)differ in terms of their pathogenesis and their preexisting background,both of which could impact the tumor immune microenvironment(TIME).However,the current understanding of the immune contexture of GC is far from complete.AIM To clarify the tumor-host immune interplay through histopathological features and the tumor immune cycle concept.METHODS In total,50 GC cases were examined(15 cases of diffuse GC,31 patients with intestinal-type GC and 4 cases of mucinous GC).The immunophenotype of GC was assessed and classified as immune desert(ID),immune excluded(IE)or inflamed(Inf)according to CD8+cell count and spatial pattern.In addition,CD68+and CD163+macrophages and programmed death-ligand 1(PD-L1)expression were estimated.RESULTS We found that GCs with different histological differentiation demonstrated distinct immune contexture.Most intestinal-type GCs had inflamed TIMEs rich in both CD8+cells and macrophages.In contrast,more aggressive diffuse-type GC more often possessed ID characteristics with few CD8+lymphocytes but abundant CD68+macrophages,while mucinous GC had an IE-TIME with a prevalence of CD68+macrophages and CD8+lymphocytes in the peritumor stroma.PD-L1 expression prevailed mostly in intestinal-type Inf-GC,with numerous CD163+cells observed.Therefore,GCs of different histological patterns have specific mechanisms of immune escape.While intestinal-type GC was more often related to PD-L1 expression,diffuse and mucinous GCs possessing more aggressive behavior demonstrated low immunogenicity and a lack of tumor antigen recognition or immune cell recruitment into the tumor clusters.CONCLUSION These data help to clarify the links between tumor histogenesis and immunogenicity for a better understanding of GC biology and more tailored patient management.

Prognostic significance of serum inflammation indices for different tumor infiltrative pattern types of gastric cancer

BACKGROUND Inflammatory indices are considered to be potential prognostic biomarkers for patients with gastric cancer(GC).However,there is no evidence defining the prognostic significance of inflammatory indices for GC with different tumor infiltrative pattern(INF)types.AIM To evaluate the significance of inflammatory indices and INF types in predicting the prognosis of patients with GC.METHODS A total of 962 patients who underwent radical gastrectomy were retrospectively selected for this study.Patients were categorized into the expansive growth type(INFa),the intermediate type(INFb),and the infiltrative growth type(INFc)groups.The cutoff values of inflammatory indices were analyzed by receiver operating characteristic curves.The Kaplan–Meier method and log-rank test were used to analyze overall survival(OS).The chi-square test was used to analyze the association between inflammatory indices and clinical characteristics.The independent risk factors for prognosis in each group were analyzed by univariate and multivariate analyses based on logistic regression.Nomogram models were constructed by R studio.RESULTS The INFc group had the worst OS(P<0.001).The systemic immune-inflammation index(P=0.039)and metastatic lymph node ratio(mLNR)(P=0.003)were independent risk factors for prognosis in the INFa group.The platelet-lymphocyte ratio(PLR)(P=0.018),age(P=0.026),body mass index(P=0.003),and postsurgical tumor node metastasis(pTNM)stage(P<0.001)were independent risk factors for prognosis in the INFb group.The PLR(P=0.021),pTNM stage(P=0.028),age(P=0.021),and mLNR(P=0.002)were independent risk factors for prognosis in the INFc group.The area under the curve of the nomogram model for predicting 5-year survival in the INFa group,INFb group,and INFc group was 0.787,0.823,and 0.781,respectively.CONCLUSION The outcome of different INF types GC patients could be assessed by nomograms based on different inflammatory indices and clinicopathologic features.

ISOLATION AND CULTURE OF TUMOR-INFILTRATING LYMPHOCYTES FROM MOUSE HEPATOMA

By uaing enzyme digestion and Flcoll- Hypaque or Percoll discontinuous density methods, we have successfully obtained tumor-infiltrating lymphocytes (TIL) from mouse hepatoma. When analyzing the purity of TIL after separation. It was found that Percoll was more effective than Flcoll (P<0. 01). TIL could be activated In the presence of recombinant lL-2 (rIL-2) and begin to expand after culturing for 5-7 days, the tumor cells tend to decrease and disappeared after 14 days or so. TIL increased 105-fold over 40 days. Conditioned medium containing supernatant of PHA and rIL- 2 stimulated syngeneic spleen cell culture could promote the expansion of TIL.

The Tumor Infiltrating Lymphocytes (TILs): Did We Find the Missed Piece of the Huge Puzzle?

Tumor infiltrating lymphocytes (TILs) are used in evaluating the prognosis and determining treatment of different types of cancer with variable degrees of success. The usage of checkpoint inhibitor immunotherapy as a treatment variety for cancer and Adoptive cell therapy is associated with many complications, severe side effects and high expenses. Recently, in a limited number of metastatic GIT and breast cancers, the identification of T-cell specific against so-called tumor neo-antigens and Adoptive transfer of those lymphocytes resulted in some improvement. In 2020, Detection of a T cell receptor (TCR) in a T cell clone that recognized and killed most human cancer cell lines in vitro via the monomorphic MHC class I-related protein MR1, offers an opportunity for pan-cancer therapy Twenty three years earlier, Moist Heat was used successfully to activate a whole different and new immune response that was able to detect genetic mutation in the affected cancer cells and cured many cases of squamous and basal cell carcinomas. In this commentary review, we aimed to revise the literature for updates of TILs usage in cancer prognosis and treatment.

Correlations between P2RX1 Expression and Gastrointestinal Cancers Prognosis and Immune Infiltration Based on Bioinformatics Analysis

This study was conducted to explore the correlations between the expression,methylation,and various clinicopathological factors of purinergic P2X1 receptor(P2RX1)and the prognosis of patients with gastrointestinal tumors.The Cancer Genome Atlas(TCGA)and the Genotype-Tissue Expression(GTEx)databases were used to analyze the expression of P2RX1 in different types of gastrointestinal cancers.Kaplan-Meier analysis and univariate Cox regression analysis were used to analyze the correlations between P2RX1 expression and the prognosis of various gastrointestinal tumors.Correlations between P2RX1 expression and N6 methyladenine(m6A)-related genes as well as immune checkpoint genes were analyzed by R packages(R version:4.0.3)based on TCGA database.The association between P2RX1 methylation level and the prognosis of patients with gastrointestinal cancers was analyzed using the MethSurv database.In order to explore the biological functions of P2RX1 in hepatocellular carcinoma,the Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)enrichment analysis were carried out using R software.In order to evaluate the correlations between P2RX1 and tumor immune infiltration,Spearman correlation test was performed.The correlations between P2RX1 expression and immune score as well as immune checkpoint genes were analyzed based on TCGA and Tumor Immune Estimation Resource(TIMER)databases.The expression of P2RX1 was found to be significantly downregulated in gastrointestinal tumors except in cholangiocarcinoma(P<0.05).High expression of P2RX1 tended to present better prognosis in hepatocellular carcinoma(P<0.05).It was noted that cg06475633 of P2RX1 presented a higher methylation level compared with other CpG sites in hepatocellular carcinoma.Overall,six CpGs of P2RX1 were associated with significant prognosis in patients with hepatocellular carcinoma(P<0.05).Among all the 20 m6A-related genes,Wilms'tumor 1-associating protein(WTAP)was the most strongly correlated with P2RX1 in hepatocellular carcinoma.Gene enrichment analysis showed that P2RX1 is widely involved in the proliferation,activation,organization,and differentiation of various immune cells.After investigating the TIMER database,P2RX1 was found to be tightly correlated with immune infiltrating cells in gastrointestinal tumors,especially with dendritic cells.Moreover,P2RX1 was found to be strongly positively associated with programmed cell death 1(PD1),programmed death-ligand 1(PD-L1),and cytotoxic T-lymphocyte-associated protein 4(CTLA4)in hepatocellular carcinoma(P<0.05).In conclusion,the dual role of P2RX1 in cancers and its involvement in the recruitment as well as regulation of tumor infiltrating cells in gastrointestinal cancers may be appreciated through this study.

Immunogenic cell death-related long noncoding RNA influences immunotherapy against lung adenocarcinoma

Lung adenocarcinoma(LUAD)is the leading cause of cancer-related deaths,accounting for over a million deaths worldwide annually.Immunogenic cell death(ICD)elicits an adaptive immune response.However,the role of ICD-related long noncoding RNAs(lncRNAs)in LUAD is unknown.In this study,we investigated the characteristics of the tumor microenvironment in LUAD,the prognostic significance of ICD-related lncRNAs,and the half-maximal inhibitory concentration(IC50)of possible chemotherapeutic drugs.We sorted prognostic lncRNAs using univariate Cox regression and constructed a risk signature based on them.We then confirmed the model’s accuracy and generated a nomogram.Additionally,we performed immune microenvironment analysis,somatic mutation calculation,Tumor Immune Dysfunction and Exclusion(TIDE)analysis,and anticancer pharmaceutical IC50 prediction.Least absolute shrinkage and selection operator Cox regression identified 27 prognostic lncRNAs related to ICD,and a unique risk signature using 10 ICD-related lncRNAs was constructed.The risk score was confirmed to be a reliable predictor of survival,with the highest c-index score.The signature had a remarkable predictive performance with clinical applicability and could accurately predict the overall survival in LUAD.Furthermore,the lncRNA signature was closely associated with immunocyte invasion.We also analyzed the correlation between the risk score,tumor-infiltrating immune cells,and prognosis and identified high immune and ESTIMATE scores in low-risk patients.Moreover,we observed elevated checkpoint gene expression and low TIDE scores in high-risk patients,indicating a good immunotherapy response.Finally,high-risk patients were shown to be susceptible to anticancer medications.Therefore,our unique risk signature comprising 10 ICD-related lncRNAs was demonstrated to indicate the characteristics of the tumor-immune microenvironment in LUAD,predict patients’overall survival,and guide individualized treatment.

Right hemicolectomy combined with duodenum-jejunum Roux-en-Y anastomosis for hepatic colon carcinoma invading the duodenum:A single-center case series

BACKGROUND Hepatic colon carcinoma invading the duodenum is not common in clinical practice.Surgical treatment of colonic hepatic cancer that invades the duodenum is difficult,and the surgical risk is high.AIM To discuss the efficacy and safety of duodenum-jejunum Roux-en-Y anastomosis for the treatment of hepatic colon carcinoma invading the duodenum.METHODS From 2016 to 2020,11 patients from Panzhihua Central Hospital diagnosed with hepatic colon carcinoma were enrolled in this study.Clinical and therapeutic effects and prognostic indicators were retrospectively analyzed to determine the efficacy and safety of our surgical procedures.All patients underwent radical resection of right colon cancer combined with duodenum-jejunum Roux-en-Y anastomosis.RESULTS The median tumor size was 65 mm(r50-90).Major complications(ClavienDindoI-II)occurred in 3 patients(27.3%);the average length of hospital stay was 18.09±4.21 d;and only 1 patient(9.1%)was readmitted during the 1st mo after the surgery.The 30-d mortality rate was 0%.After a median follow-up of 41 m(r7-58),the disease-free survival at 1,2,and 3 years was 90.9%,90.9%and 75.8%,respectively;the overall survival at 1,2,and 3 years was 90.9%.CONCLUSION In selected patients,radical resection of right colon cancer combined with duodenum-jejunum Roux-en-Y anastomosis is clinically effective,and the complications are manageable.The surgical procedure also has an acceptable morbidity rate and mid-term survival.

Aconite aqueous extract inhibits the growth of hepatocellular carcinoma through CCL2-dependent enhancement of natural killer cell infiltration

Objective:Aconite is a traditional Chinese herbal medicine that has been found to inhibit the development of liver cancer;however,its exact molecular mechanisms in this process remain unclear.This study explores how aconite aqueous extract(AAE)inhibits hepatocellular carcinoma(HCC).Methods:An in vivo mouse model of subcutaneous liver cancer was established.After AAE treatment,immunohistochemistry(IHC)was used to determine the effect of AAE on natural killer(NK)cells.Subsequently,C57BL/6 mice were used to establish the subcutaneous tumor model,and a group of these mice were treated with anti-PK163 antibody to remove NK cells,which was verified by flow cytometry and IHC.The effect of AAE on the proliferation of HCC cells in vitro was determined using cell counting kit-8.The effect of AAE on chemokine production in HCC cells was measured using real-time quantitative polymerase chain reaction and an enzyme-linked immunosorbent assay.The effect of AAE on the migration of NK cells was determined using a transwell assay.Finally,the molecular mechanism was investigated using the Western blotting method.Results:We demonstrated that the ability of AAE to induce overexpression of the cytokine C–C motif chemokine ligand 2(CCL2)in HCC cells is fundamental to the infiltration of NK cells into the tumor bed.Mechanistically,we found that the upregulation of CCL2 was achieved by the activation of c-Jun Nterminal kinase but not extracellular regulated protein kinase or p38.Conclusion:Our findings suggest that AAE can be used as an effective immune adjuvant to enhance antitumor immunity by increasing NK cell infiltration into tumors,which could help to improve the efficacy of HCC treatments.

Pathological significance of abnormal recepteur d'origine nantais and programmed death ligand 1 expression in colorectal cancer

BACKGROUND Programmed death ligand 1(PD-L1) immunotherapy remains poorly efficacious in colorectal cancer(CRC). The recepteur d'origine nantais(RON) receptor tyrosine kinase plays an important role in regulating tumor immunity.AIM To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC.METHODS Gene expression data from the Gene Expression Omnibus database(GEO;n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine(FAHZUSM;n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot.RESULTS In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121(32%), 43(11%), 91(24%), and 51(13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment(P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells.CONCLUSION RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.

Development of a prognostic signature for esophageal cancer based on a novel 7-DNA damage repair genes signature

Esophageal cancer(EC)was an aggressive malignant neoplasm characterized by high morbidity and poor prognosis.Identifying the changes in DNA damage repair genes helps to better understand the mechanisms of carcinoma progression.In this study,by comparing EC samples and normal samples,we found a total of 132 DDR expression with a significant difference.Moreover,we revealed higher expression of POLN,PALB2,ATM,PER1,TOP3B and lower expression of HMGB1,UBE2B were correlated to longer OS in EC.In addition,a prognostic risk score based on 7 DDR gene expression(POLN,HMGB1,TOP3B,PER1,UBE2B,ATM,PALB2)was constructed for the prognosis of EC.Meanwhile,EC cancer samples were divided into 3 subtypes based on 132 DDR genes expressions.Clinical profile analysis showed cluster C1 and C2 showed a similar frequency of T2,which was remarked higher than that in cluster 3.Moreover,we found the immune cell inflation levels were significantly changed in different subtypes of EC.The infiltration levels of T cell CD8+,B cell and NK cells were greatly higher in cluster 2 than that in cluster 1 and cluster 3.The results showed T cell CD4+infiltration levels were dramatically higher in cluster 1 than that in cluster 2 and cluster 3.Finally,we perform bioinformatics analysis of DEGs among 3 subtypes of EC and found DDR genes may be related to multiple signaling,such as Base excision repair,Cell cycle,Hedgehog signaling pathway,and Glycolysis/Gluconeogenesis.These results showed DDR genes may serve as new target for the prognosis of EC and prediction of the potential response of immune therapy in EC.

“Six-and-twelve” score for outcome prediction of hepatocellular carcinoma following transarterial chemoembolization. In-depth analysis from a multicenter French cohort

The“six-and-twelve”(6&12)score is a new hepatocellular carcinoma(HCC)prognostic index designed for recommended transarterial chemoembolization(TACE)candidates.Quick and easy to use by the sum of tumor size(cm)and number,this model identifies three groups with different survival time(the sum is≤6;or>6 but≤12;or>12);a survival benefit with TACE can be expected for HCC patients with a score not exceeding twelve.Recently,Wang ZW et al showed that the“6&12”model was the best system correlated with radiological response after the first TACE.Thus,we wanted to assess its survival prediction ability as well as its prognostic value and compared it to other systems(Barcelona Clinic Liver Cancer,Hong Kong Liver Cancer(HKLC)staging,Albumin-Bilirubin grade,tumor nodularity,infiltrative nature of the tumor,alpha-fetoprotein,Child-Pugh class,and Performance Status score,Cancer of the Liver Italian Program,Model to Estimate Survival for HCC scores,up-to-seven criteria)different from Wang ZW et al study in a multicenter French cohort of HCC including only recommended TACE candidates retrospectively enrolled.As previously demonstrated,we show that the"6&12”score can classify survival within this French cohort,with a prognostic value comparable to that of other systems,except HKLC staging.More importantly,the“6&12”score simplicity and ability in patients’stratification outperform other systems for a routine clinical practice.

Tumor-infiltrating lymphocytes in the immunotherapy era

The clinical success of cancer immune checkpoint blockade(ICB)has refocused attention on tumor-infiltrating lymphocytes(TILs)across cancer types.The outcome of immune checkpoint inhibitor therapy in cancer patients has been linked to the quality and magnitude of T cell,NK cell,and more recently,B cell responses within the tumor microenvironment.State-of-the-art single-cell analysis of TIL gene expression profiles and clonality has revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune activation and exhaustion.Many of these states are conserved across tumor types,in line with the broad responses observed clinically.Despite this homology,not all cancer types with similar TIL landscapes respond similarly to immunotherapy,highlighting the complexity of the underlying tumor-immune interactions.This observation is further confounded by the strong prognostic benefit of TILs observed for tumor types that have so far respond poorly to immunotherapy.Thus,while a holistic view of lymphocyte infiltration and dysfunction on a single-cell level is emerging,the search for response and prognostic biomarkers is just beginning.Within this review,we discuss recent advances in the understanding of TIL biology,their prognostic benefit,and their predictive value for therapy.