Predictive value of tumor-infiltrating lymphocytes for neoadjuvant therapy response in triple-negative breast cancer: A systematic review and meta-analysis

BACKGROUND The association between tumor-infiltrating lymphocyte(TIL)levels and the res-ponse to neoadjuvant therapy(NAT)in patients with triple-negative breast cancer(TNBC)remains unclear.AIM To investigate the predictive potential of TIL levels for the response to NAT in TNBC patients.METHODS A systematic search of the National Center for Biotechnology Information PubMed database was performed to collect relevant published literature prior to August 31,2023.The correlation between TIL levels and the NAT pathologic com-plete response(pCR)in TNBC patients was assessed using a systematic review and meta-analysis.Subgroup analysis,sensitivity analysis,and publication bias analysis were also conducted.RESULTS A total of 32 studies were included in this meta-analysis.The overall meta-ana-lysis results indicated that the pCR rate after NAT treatment in TNBC patients in the high TIL subgroup was significantly greater than that in patients in the low TIL subgroup(48.0%vs 27.7%)(risk ratio 2.01;95%confidence interval 1.77-2.29;P<0.001,I2=56%).Subgroup analysis revealed that the between-study hetero-geneity originated from differences in study design,TIL level cutoffs,and study populations.Publication bias could have existed in the included studies.The meta-analysis based on different NAT protocols revealed that all TNBC patients with high levels of TILs had a greater rate of pCR after NAT treatment in all protocols(all P≤0.01),and there was no significant between-protocol difference in the statistics among the different NAT protocols(P=0.29).Additionally,sensitivity analysis demonstrated that the overall results of the meta-analysis remained consistent when the included studies were individually excluded.CONCLUSION TILs can serve as a predictor of the response to NAT treatment in TNBC patients.TNBC patients with high levels of TILs exhibit a greater NAT pCR rate than those with low levels of TILs,and this predictive capability is con-sistent across different NAT regimens.

Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma(HCC)whose treatment options are limited.However,the long-term patient response to drugs and the survival outcomes remain a concern.With increasing exploration of the HCC microenvironment,particularly in terms of T lymphocyte immunity,a new era of immunomolecular targeted therapy,based on molecular signaling,has arrived for advanced HCC.In the study of immune tolerance of the intrinsic HCC microenvironment,we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors,such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy,have improved clinical outcomes in some patients with advanced HCC.Furthermore,various combination therapies have been investigated,and HCC types have been categorized into different types based on anti–programmed cell death protein 1(PD-1)/ligand of programmed cell death protein 1(PD-L1)treatment.In this paper,we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC.We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy.Thereafter,we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors,anti–T lymphocyte–related signaling pathways in HCC,and other anti-CD8+T cell immune checkpoints.In this way,this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC,in order to provide better individualized treatments for patients with advanced HCC.

Prognostic and immunological roles of heat shock protein A4 in lung adenocarcinoma

BACKGROUND Heat shock protein A4(HSPA4)belongs to molecular chaperone protein family which plays important roles within variable cellular activities,including cancer initiation and progression.However,the prognostic and immunological significance of HSPA4 in lung adenocarcinoma(LUAD)has not been revealed yet.AIM To explore the prognostic and immunological roles of HSPA4 to identify a novel prognostic biomarker and therapeutic target for LUAD.METHODS We assessed the prognostic and immunological significance of HSPA4 in LUAD using data from The Cancer Genome Atlas database.The association between HSPA4 expression and clinical-pathological features was assessed through Kruskal-Wallis and Wilcoxon signed-rank test.Univariate/multivariate Cox regression analyses and Kaplan-Meier curves were employed to evaluate prognostic factors,including HSPA4,in LUAD.Gene set enrichment analysis(GSEA)was conducted to identify the key signaling pathways associated with HSPA4.The correlation between HSPA4 expression and cancer immune infiltration was evaluated using single-sample gene set enrichment analysis(ssGSEA).RESULTS Overexpressing HSPA4 was significantly related to advanced pathologic TNM stage,advanced pathologic stage,progression disease status of primary therapy outcome and female subgroups with LUAD.In addition,increased HSPA4 expression was found to be related to worse disease-specific survival and overall survival.GSEA analysis indicated a significant correlation between HSPA4 and cell cycle regulation and immune response,particularly through diminishing the function of cytotoxicity cells and CD8 T cells.The ssGSEA algorithm showed a positive correlation between HSPA4 expression and infiltrating levels of Th2 cells,while a negative correlation was observed with cytotoxic cell infiltration levels.CONCLUSION Our findings indicate HSPA4 is related to prognosis and immune cell infiltrates and may act as a novel prognostic biomarker and therapeutic target for LUAD.

Revolutionizing gastric cancer treatment:The potential of immunotherapy

Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

Comprehensive assessment of the association between tumorinfiltrating immune cells and the prognosis of renal cell carcinoma

BACKGROUND According to current statistics,renal cancer accounts for 3%of all cancers world-wide.Renal cell carcinoma(RCC)is the most common solid lesion in the kidney and accounts for approximately 90%of all renal malignancies.Increasing evi-dence has shown an association between immune infiltration in RCC and clinical outcomes.To discover possible targets for the immune system,we investigated the link between tumor-infiltrating immune cells(TIICs)and the prognosis of RCC.AIM To investigate the effects of 22 TIICs on the prognosis of RCC patients and iden-tify potential therapeutic targets for RCC immunotherapy.METHODS The CIBERSORT algorithm partitioned the 22 TIICs from the Cancer Genome Atlas cohort into proportions.Cox regression analysis was employed to evaluate the impact of 22 TIICs on the probability of developing RCC.A predictive model for immunological risk was developed by analyzing the statistical relationship between the subpopulations of TIICs and survival outcomes.Furthermore,multi-variate Cox regression analysis was used to investigate independent factors for the prognostic prediction of RCC.A value of P<0.05 was regarded as statistically significant.RESULTS Compared to normal tissues,RCC tissues exhibited a distinct infiltration of im-mune cells.An immune risk score model was established and univariate Cox regression analysis revealed a significant association between four immune cell types and the survival risk connected to RCC.High-risk individuals were correlated to poorer outcomes according to the Kaplan-Meier survival curve(P=1E-05).The immunological risk score model was demonstrated to be a dependable predictor of survival risk(area under the curve=0.747)via the receiver operating characteristic curve.According to multivariate Cox regression analysis,the immune risk score model independently predicted RCC patients'prognosis(hazard ratio=1.550,95%CI:1.342–1.791;P<0.001).Finally,we established a nomogram that accurately and comprehensively forecast the survival of patients with RCC.CONCLUSION TIICs play various roles in RCC prognosis.The immunological risk score is an independent predictor of poor survival in kidney cancer cases.

Prognostic significance of tumor budding,desmoplastic reaction,and lymphocytic infiltration in patients with gastric adenocarcinoma

BACKGROUND Recent studies have shown that the tumor microenvironment significantly influences the behavior of solid tumors.In this context,Accumulated data suggests that pathological evaluation of tumor budding(TB),desmoplastic reaction(DR),and tumor-infiltrating lymphocytes(TILs)may be crucial in determining tumor behavior in the gastrointestinal tract.Regarding gastric adenocarcinoma(GAC),although some results suggest that TB and TILs may be effective in determining the course of the disease,the data do not agree.Moreover,very few studies have investigated the relationship between DR and survival.At present,the associations between tumor TB,DR and TILs in GAC patients have not been determined.AIM To establish the relationships between TB,DR,and TILs in patients with GAC and to assess their influence on prognosis.METHODS Our study group comprised 130 patients diagnosed with GAC.The definition of TB was established based on the International TB Consensus Conference.The DR was categorized into three groups according to the level of tumor stroma maturation.The assessment of TILs was conducted using a semiquantitative approach,employing a cutoff value of 5%.The statistical analysis of the whole group and 100 patients with an intestinal subtype of GAC was performed using SPSS version 27.RESULTS A significant correlation between peritumoral budding(PTB)and intratumoral budding(ITB)was noted(r=0.943).Tumors with high PTBs and ITBs had a greater incidence of immature DRs and low TILs(P<0.01).PTB and ITB were associated with histological subtype,lymph node metastasis(LNM),and stage(P<0.01).ITB,PTB,LNM,DR,and stage were significant risk factors associated with poor prognosis.The multivariate Cox regression analysis identified ITB,PTB,and LNM as independent prognostic variables(P<0.05).In intestinal-type adenocarcinomas,a positive correlation between PTB and ITB was noted(r=0.972).While univariate analysis revealed that LNM,stage,PTB,ITB,and DR were strong parameters for predicting survival(P<0.05),only PTB and ITB were found to be independent prognostic factors(P<0.001).CONCLUSION TB may be a potential prognostic marker in GAC.However,further studies are needed to delineate its role in pathology reporting protocols and the predictive effects of DR and TILs.

LAG-3 expression on tumor-infiltrating T cells in soft tissue sarcoma correlates with poor survival

Objective: To elucidate the role and prognostic significance of lymphocyte activation-gene-3(LAG-3) in soft tissue sarcoma(STS).Methods: The expression of LAG-3 in patient and matched normal blood samples was analyzed by flow cytometry. The localization and prognostic values of LAG-3^+ cells in 163 STS patients were analyzed by immunohistochemistry. In addition, the expression of tumor-infiltrating CD3^+ T, CD4^+ T, and CD8^+ T cells and their role in the prognosis of STS were evaluated by immunohistochemistry. The effect of LAG-3 blockade was evaluated in an immunocompetent MCA205 fibrosarcoma mouse model.Results: Peripheral CD8^+ and CD4^+ T cells from STS patients expressed higher levels of LAG-3 than those from healthy donors.LAG-3 expression in STS was significantly associated with a poor clinical outcome(P = 0.038) and was correlated with high pathological grade(P < 0.001), advanced tumor stage(P = 0.016). Additionally, LAG-3 expression was highly correlated with CD8^+ T-cell infiltration(r = 0.7034, P < 0.001). LAG-3 was expressed in murine tumor-infiltrating lymphocytes, and its blockade decreased tumor growth and enhanced secretion of interferon-gamma by CD8^+ and CD4^+ T cells.Conclusions: LAG-3 blockade may be a promising strategy to improve the effects of targeted therapy in STS.

Clinical significance of tumor-infiltrating lymphocytes for gastric cancer in the era of immunology

Immunotherapy has begun to revolutionize cancer treatment, by introducing therapies that target the host immune system instead of the tumor, therapies that possess unique adverse event profiles, and therapies that may cure certain types of cancer. The immune microenvironment of tumors is emerging as the most important means of understanding the relationship between a patient' immune system and their cancer, informing prognosis, and guiding immunotherapy, such as an antibody blockade of immune checkpoints. For some solid tumors, simple quantitation of lymphocyte infiltration would seem to have prognostic significance, suggesting that lymphocyte infiltration is not passive but may actively promote or inhibit tumor growth. For gastric cancers, several studies have provided strong evidence that immune cells contribute to determining prognosis. However, the exact role of immune cells in gastric cancer remains unclear. Therefore, this review focuses on the clinical significance of immune cells, especially tumor-infiltrating lymphocytes, in gastric cancer.

Association between Up-regulation of Fas Ligand Expression and Apoptosis of Tumor-infiltrating Lymphocytes in Human Breast Cancer

In order to study the significance of FasL expression in immune escape of breast cancer, FasL protein expression and the number of tumor-infiltrating lymphocytes （TILs） in 40 specimens of breast cancer were detected by immunohistochemitry. The expression of FasL mRNA was measured by in situ hybridization in the consecutive tissue slices of 40 breast cancers respectively. By using terminal deoxynucleotidyl transferase-mediaed dUTP nick end labeling （TUNEL）, apoptotic cells were detected in 40 specimens of breast cancer. The expression of FasL was detected in all 40 specimens to varying degrees. In the consecutive tissue slices, the location of expression of FasL protein corresponded with that of FasL mRNA. In those with FasL extensive expression, the number of TILs was less （P〈0.05）, the apoptotic index （AI） of TILs was higher and the AI of tumor cells was lower （P〈0.01） than those with FasL weak expression respectively. The AI of TILs was correlated with that of tumor cells （r=-0.629, P〈0.01）. In conclusion, breast cancer cells can induce the apoptosis of TILs through the expression of FasL, which can counterattack the immune system. This may be a mechanism of immune evasion in breast cancer.

Tumor-infiltrating platelets predict postoperative recurrence and survival in resectable pancreatic neuroendocrine tumor

BACKGROUND Platelets have been reported to participate in tumor cell growth,extravasation,epithelial–mesenchymal transition,metastasis,and drug resistance.However,the importance of platelets in pancreatic neuroendocrine tumor(pNET)lacks adequate literature support.The predictive value of tumor-infiltrating platelets(TIPs)in pNET remains unclear.AIM To investigate the relationship between TIPs and the prognosis of patients with pNET following radical resection.METHODS In total,113 patients who had undergone radical surgical resection with a pathologic diagnosis of pNET were enrolled in this study.Immunohistochemical analysis of cluster of differentiation 42b(CD42b)expression in the tumor specimens was performed to determine the presence of TIPs.Univariate and multivariate analyses were used to analyze the prognostic value of TIPs.RESULTS TIPs were observed in intratumoral areas in 54 patients.Neither basic characteristics nor preoperative platelet-associated indicators showed a significant relationship with the presence of TIPs(all P>0.05).Patients with positive intratumoral CD42b expression had worse overall survival(P=0.005)and recurrence-free survival(P<0.001)than those with negative intratumoral CD42b expression.Multivariate analysis demonstrated that TIPs were independent prognostic factors for overall survival(P=0.049)and recurrencefree survival(P=0.003).Nevertheless,platelet count,mean platelet volume,and platelet-to-lymphocyte ratio were not associated with postoperative survival or recurrence in pNET patients(all P>0.05).CONCLUSION TIPs are a useful prognostic biomarker for patients with resectable pNET,and their detection represents a promising tool for pNET treatment strategy decisions.

Heterogeneity of tumor-infiltrating myeloid cells in era of single-cell genomics

Tumor microenvironment(TME)is highly heterogeneous and composed of complex cellular components,including multiple kinds of immune cells.Among all immune cells in TME,tumor-infiltrating myeloid cells(TIMs)account for a large proportion and play roles as key regulators in a variety of functions,ranging from immune-mediated tumor killing to tumor immune evasion.Understanding the heterogeneity of TIMs will provide valuable insights for new therapeutic targeting of myeloid cells.Single-cell genomic technologies deciphering cell composition and gene expression at single-cell resolution have largely improved our understanding of the cellular heterogeneity of TIMs and highlighted several novel cell subtypes contributing to the variation of patient survival and treatment response.However,these cell subtypes were defined based on limited data without a concordant nomenclature,which makes it difficult to understand whether they exist in different studies.Thus,in this review,we comprehensively summarized the common agreements and current different opinions on the heterogeneity of TIMs gained from single-cell studies;evaluated the feasibility of current myeloid cell targets at single-cell level and proposed a uniform nomenclature for TIM subsets.

Prognostic implications of tumor-infiltrating lymphocytes in association with programmed cell death ligand 1 expression in remnant gastric cancer

Objective:Remnant gastric cancer(RGC)is usually associated with a worse prognosis.As they are less common and very heterogeneous tumors,new prognostic and reliable determinants are required to predict patients’clinical course for RGC.This study aimed to investigate the tumor-infiltrating lymphocytes(TILs)and programmed cell death ligand 1(PD-L1)status as prognostic biomarkers in a cohort of patients with RGC to develop an immunerelated score.Methods:Patients with gastric cancer(GC)who underwent curative intent gastrectomy were retrospectively investigated.RGC resections with histological diagnosis of gastric adenocarcinoma were enrolled in the study.The risk score based on immune parameters was developed using binary logistic regression analysis.RGCs were divided into high-risk(HR),intermediate-risk(IR),and low-risk(LR)groups based on their immune score.The markers(CD3+,CD4+/CD8+T cells and PD-L1)were selected for their potential prognostic,therapeutic value,and evaluated by immunohistochemistry(IHC).Results:A total of 42 patients with RGC were enrolled in the study.The score based on immune parameters exhibited an accuracy of 79%[the area under the receiver operating characteristic curve(AUC)=0.79,95%confidence interval(95%CI),0.63-0.94,P=0.002],and the population was divided into 3 prognostic groups:10(23.8%)patients were classified as LR,15(35.7%)as IR,and 17(40.5%)as HR groups.There were no differences in clinicopathological and surgical characteristics between the three groups.In survival analysis,HR and IR groups had worse disease-free survival and overall survival rates compared to the LR group.In the multivariate analysis,lymph node metastasis and the immune score risk groups were independent factors related to worse survival.Conclusions:A scoring system with immune-related markers was able to distinguish prognostic groups of RGC associated with survival.Accordingly,tumor-infiltrating immune lymphocytes and PD-L1 status may serve as a potential prognostic biomarker for patients with RGC.

Change of tumor-infiltrating lymphocyte of associating liver partition and portal vein ligation for staged hepatectomy for hepatocellular carcinoma

BACKGROUND The role of tumor-infiltrating lymphocytes(TILs)in the growth and progression of hepatocellular carcinoma(HCC)has attracted widespread attention.AIM To evaluate the feasibility of associating liver partition and portal vein ligation for staged hepatectomy(ALPPS)for massive HCC by exploring the role of TIL in the tumor microenvironment.METHODS Fifteen massive HCC patients who underwent ALPPS treatment and 46 who underwent hemi-hepatectomy were selected for this study.Propensity score matching was utilized to match patients in ALPPS and hemi-hepatectomy groups(1:1).Quantitative analysis of TILs in tumor and adjacent tissues between the two groups was performed by immunofluorescence staining and further analyses with oncological characteristics.In the meantime,trends of TILs in peripheral blood RESULTS Continuous measurement of tumor volume and necrosis volume showed that the proportion of tumor necrosis volume on the seventh day after stage-I ALPPS was significantly higher than the pre-operative value(P=0.024).In the preoperative period of stage-I ALPPS,the proportion of tumor necrosis volume in the high CD8+T cell infiltration group was significantly higher than that in the low group(P=0.048).CONCLUSION TIL infiltration level maintained a dynamic balance during the preoperative period of ALPPS.Compared with right hemi-hepatectomy,the ALPPS procedure does not cause severe immunosuppression with the decrease in TIL infiltration and pathological changes in immune components of peripheral blood.Our results suggested that ALPPS is safe and feasible for treating massive HCC from the perspective of immunology.In addition,high CD8+T cell infiltration is associated with increasing tumor necrosis in the perioperative period of ALPPS.

Tumor-infiltrating B cells come into vogue

Lymphocyte infiltration into solid tumors has been recognized as a main determinator of positive prognosis.For the most part this is attributed to cytotoxic T cells capable of directly destroying malignant cells.However,when considering the complex composition of the human immune system,recent findings of Nielsenet al on a potentially central role of tumor-infiltrating B cells is not really surprising.In this commentary article,I want to highlight the enormous potential impact of this observation for basic and translational research,prognostic procedures and ultimately for the development of future therapeutic concepts.

IN VITRO ANTITUMOR ACTIVITY OF TUMOR-INFILTRATING LYMPHOCYTES FROM HUMAN GASTRIC CARCINOMA

Tumor-infiltrating lymphocytes (TIL) isolated from 11 gastric carcinoma were studied. TIL could grow for a long-term in medium containing recombi-nant interleukin-2(rlL-2). The mean expansion fold achieved in 6 long-term cultures of 11 specimens was 15.1. RIL-2 expanded gastric TIL exhibited significant cytotoxicity against K562, BGC823, MCF-7 and more effective antitumor cytotoxicity against fresh autologous tumor targets and human gastric cancer cell line. Peak cytotoxicity was shown in the third or fourth week after cultures. Cryopreservation of gastric TIL didn't influence their expansion capacity and antitumor activity. Phenotypic analysis was demonstrated in this study. The results of present study indicate that TIL from human gastric carcinoma could be expanded and reach high levels of antitumor effector function in long-term cultures with rIL-2. Their function may be of clinical importance.

Prognosis and immunological role of HLA-DMA in lung adenocarcinoma

Background:HLA-DMA presents pathogen-derived antigens to CD4+and CD8+T cells,respectively,and plays a significant part in initiating the immune response.So far,the impact of HLA expression on the prognosis of BC cells is controversial,because few studies have shown that the expressions of some HLA genes are related to the improvement of the survival rate.Up till now,however,the relationship between HLA-DMA and LUAD has not yet been assessed.Methods:We analyzed the TCGA database and assessed the prognostic value of HLA-DMA in LUAD.We conducted the Kruskal–Wallis and Wilcoxon signed-rank test and utilized logistic regression to assess the role of clinical-pathologic characteristics and HLA-DMA expression.Kaplan–Meier method and the multivariate and univariate Cox regression were also used for evaluating the prognosis-related factors of LUAD.GSEA was used to identify HLA-DMA-related key pathways.The ssGSEA of the TCGA data was used to investigate the correlations between HLA-DMA and cancer immune cell infiltration.Results:Low HLA-DMA expression was related to poorer disease-specific survival(DSS)and overall survival(OS)of LUAD patients.GSEA revealed that HLA-DMA was tightly interrelated with an immune response by the reactome activation of anterior hox genes in hindbrain development during the early embryogenesis signaling pathway.The expression of HLA-DMA was positively associated with cytotoxic cell infiltration and negatively related to the Th2 cell infiltration according to the ssGSEA.Western blotting and the CCK-8 assay showed that KD-HLA-DMA could significantly increase the proliferation of A549 cells and significantly reduce cell pyroptosis.Conclusion:All the observations implied that HLA-DMA was associated with patient prognosis and immune infiltration in LUAD.

Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment

BACKGROUND Comprehensive genomic analysis has shown that small bowel adenocarcinoma(SBA)has different genomic profiles from gastric and colorectal cancers.Hence,it is essential to establish chemotherapeutic regimens based on SBA characteristics.The expression of programmed cell death-ligand 1(PD-L1)and programmed cell death-ligand 2(PD-L2)in SBA is not fully understood.Anti-PD-L1/PD-1 therapy uses tumor-infiltrating lymphocytes(TILs);therefore,the status of TILs in the tumor microenvironment(TME)may influence their efficacy.The ratio of FoxP3+to CD8+T cells has been reported to be useful in predicting the prognosis of digestive system cancers.AIM To investigate the clinicopathological significance of PD-L1/2 expression according to the status of TILs in SBA tissues.METHODS We performed immunohistochemical analysis for PD-L1,PD-L2,CD8,FoxP3,and DNA mismatch repair(MMR)proteins using formalin-fixed,paraffin-embedded tissues from 50 patients diagnosed with primary SBA.The immunoreactivities of PD-L1 and PD-L2 were determined separately in tumor cells and tumor-infiltrating immune cells throughout the tumor center and invasive margins,and finally evaluated using the combined positive score(CPS).We assessed CD8+and FoxP3+T cells in the intratumoral and tumor-surrounding stroma.Subsequently,we calculated and summed the ratio of FoxP3 to CD8+T cell counts.Immune-related cell densities were graded as low or high.Immunohistochemical results were compared with clinicopathological factors and patient prognosis.The distribution of cancer-specific survival(CSS)was estimated using the Kaplan–Meier method,and the log-rank test was used to test for significant differences in CSS.A Cox proportional hazard model was also used to assess the effect of tumor variables on CSS.RESULTS PD-L1 expression was positive in 34%in tumor cells(T-PD-L1)and 54%in tumor-infiltrating immune cells(I-PDL1)of the cases examined.T-PD-L2 was positive in 34%and I-PD-L2 was positive in 42%of the cases.PD-L1 CPS≥10 and PD-L2 CPS≥10 were observed in 50%and 56%of the cases,respectively.Deficient MMR(dMMR)was 14%of the cases.T-PD-L1,I-PD-L1 and PD-L1 CPS≥10 were all significantly associated with dMMR(P=0.037,P=0.009,and P=0.005,respectively).T-PD-L1,I-PD-L1,and PD-L1 CPS≥10 were all associated with deeper depth of invasion(P=0.001,P=0.024,and P=0.002,respectively).I-PD-L2 expression and PD-L2 CPS≥10 were significantly higher in the differentiated histological type(P=0.015 and P=0.030,respectively).The I-PD-L1 and IPD-L2 levels were significantly associated with better CSS(P=0.037 and P=0.015,respectively).CD8-high was significantly associated with less lymph node metastasis(P=0.047),less distant metastasis(P=0.024),less peritoneal dissemination(P=0.034),and earlier TNM stage(P=0.047).The CD8-high group had better prognosis than the CD8-low group(P=0.018).FoxP3 expression was not associated with any clinicopathological factors or prognosis.We found that patients with PD-L2 CPS≥10 tended to have worse prognosis in the FoxP3/CD8-low group(P=0.088).CONCLUSION The clinicopathological significance of PD-L1/2 expression may differ depending on the TME status.Immune checkpoint inhibitors may improve the prognosis of SBA patients with low FoxP3/CD8 ratio and PD-L2 expression.

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.

MMP1 Is a Prognostic-Related Biomarker and Correlated with Immune Infiltration in Breast Cancer

Background: Matrix metalloproteinases 1 (MMP1) plays a role in cancer development and metastasis and high expression of MMP1 has been confirmed in various types of cancers. However, the correlation between MMP1 and prognosis and tumor-infiltration lymphocytes in breast cancer remains uncertain. In this present study, we analyzed MMP1 expression and correlation with prognosis of cancer patients in databases such as Oncomine, PrognoScan, and Kaplan-Meier plotter. In addition, we investigated the correlation of MMP1 with tumor-infiltrating immune cells in the different tumor microenvironments via Tumor Immune Estimation Resource (TIMER). Methods: MMP1 expression was analyzed via the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. The prognosis of MMP1 on cancers was analyzed using Kaplan-Meier plotter, the PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations between MMP1 and cancer immune infiltration were investigated by TIMER. In addition, correlations betweenMMP1 expression and gene marker sets of immune infiltration were analyzed by TIMER and GEPIA. Results: MMP1 is highly expressed in most cancers and correlated to poor prognosis. MMP1 expression is significantly linked with a poorer prognosis in breast cancer (OS HR 1.78, 95% CI = 1.59 - 1.98, P −0.134, P = 2.17e-05), macrophage (R = 0.41, P = 1.11e-08), dendritic cell (R = 0.221, P = 2.92e-03) and NK cell (R = 0.213, P = 4.15e-03). Besides, MMP1 expression is significantly associated with the marker genes of immune cells (P Conclusions: Our study indicates that MMP1 is correlated with prognosis and immune infiltrating levels of CD8+ T cell, CD8+ T cell, macrophage, dendritic cell and NK cells in breast cancer. Besides, MMP1 expression potentially contributes to regulation of T cell, B cell, tumor-associated macrophages (TAMs), DCs, T cell exhaustion and Tregs in colon and gastric cancer. The results indicate that MMP1 can be used as a prognostic biomarker for determining prognosis and immune infiltration in breast cancer.

Colon cancer and the immune system:The role of tumor invading T cells

Colon cancer is still one of the leading causes of cancer death worldwide. Although the host immune system has been shown to react against tumor cells, mainly through tumor infi ltrating lymphocytes and NK cells, tumor cells may utilize different ways to escape anti-tumor immune response. Tumor infi ltration of CD8+ and CD4+ (T-bet+) effector T cells has been attributed to a beneficial outcome, and the enhancement of T cell activation through T cell receptor stimulation and co-stimulatory signals provides promising strategies for immunotherapy of colon cancer. Growing evidence supports a role for the Fas/FasL system in tumor immunology, although the mechanisms and consequences of FasL activation in colon cancer are not completely understood. In animal models, depletion of regulatory T cells (CD4+ CD25+ T cells) can enhance the anti-tumor immune response under certain conditions. Taken together, recent insights in the immune reaction against colon carcinoma have provided new approaches to immunotherapy, although much remains to be learned about the exact mechanisms.