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.

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.

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.

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.

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.

IMMUNOLOGIC CHARACTER OF TUMOR INFILTRATING LYMPHOCYTES IN OVARIAN CARCINOMA

Objective: To study immunologic character of tumor-infiltrating lymphocytes (TIL) on postin vitro expansion in ovarian carcinoma, and evaluate the prospects by adopting TIL treatment of ovarian carcinoma at an advanced stage. Methods: Cellular phenotype changes in TIL were analyzed by flow cytometry. By means of molecular biology and immunologic methods, ability to secrete cytokines and anti-tumor activities of in TIL was studied. Results: Difference of cellular phenotypes in TIL was probably related to the type, feature and resource of the tumor. TIL obtained from phoroplast and parenchyma was dominant in CD3+CD4+. TIL obtained from tumor tissues, around microvessels and ascitic fluid was dominant in CD3+CD8 Concentration of rIL-2in vitro played a significant role in immunologic character of TIL. By means of rIL-2 expansionin vitro, TIL has apparently been improved in competence of secreting some cytokines, such as IL-2, TNF-α, IFN-γ, and anti-tumor activities. The activated TIL was more stimulated by further adding anti-CD3 or PHA (suitable concentration), which significantly increased its ability to secrete cytokines. Treatment with TIL+CTX or TIL+ rIL-2, could apparently improve phenotypes in peripheral blood of patients, with definitive effects. Conclusion: Immunologic activities of TILin vitro are apparently improved by rIL2 expansion. Regression of tumor, by means of infusion TIL, is not largely attributed to direct cytotoxicity to tumor cells, but indirectly and partly augmenting cellular activities and abilities of immunomodulation in patients with ovarian carcinoma being dependent on secreting multiple cytokines.

Tumor infiltrating lymphocytes in triple negative breast cancer receiving neoadjuvant chemotherapy

AIM To determine influence of neoadjuvant-chemotherapy(NAC) over tumor-infiltrating-lymphocytes(TIL) intriple-negative-breast-cancer(TNBC).METHODS TILs were evaluated in 98 TNBC cases who came to Instituto Nacional de Enfermedades Neoplasicas from 2005 to 2010. Immunohistochemistry staining for CD3, CD4, CD8 and FOXP3 was performed in tissue microarrays(TMA) sections. Evaluation of H/E in full-face and immunohistochemistry in TMA sections was performed in pre and post-NAC samples. STATA software was used and P value < 0.05 was considered statistically significant. RESULTS Higher TIL evaluated in full-face sections from pre-NAC tumors was associated to pathologic-complete-response(pCR)(P = 0.0251) and outcome(P = 0.0334). TIL evaluated in TMA sections showed low level of agreement with full-face sections(ICC = 0.017-0.20) and was not associated to pCR or outcome. TIL in post-NAC samples were not associated to response or outcome. PostNAC lesions with pC R had similar TIL levels than those without pCR(P = 0.6331). NAC produced a TIL decrease in full-face sections(P < 0.0001). Percentage of TIL subpopulations was correlated with their absolute counts. Higher counts of CD3, CD4, CD8 and FOXP3 in pre-NAC samples had longer disease-free-survival(DFS). Higher counts of CD3 in pre-NAC samples had longer overallsurvival. Higher ratio of CD8/CD4 counts in pre-NAC was associated with pCR. Higher ratio of CD4/FOXP3 counts in pre-NAC was associated with longer DFS. Higher counts of CD4 in post-NAC samples were associated with pCR.CONCLUSION TIL in pre-NAC full-face sections in TNBC are correlated to longer survival. TIL in full-face differ from TMA sections, absolute count and percentage analysis of TIL subpopulation closely related.

Effects of“Moxibustion Serum”on Proliferation and Phenotypes of Tumor Infiltrating Lymphocytes

Tumor infiltrating lymphocytes (TIL) were cultured with “moxibustion serum”(MS), and the results were examined by flow cytometry. The results indicated that MS could enhance the proliferation of TIL,accelerate it to reach the exponential growth phase, and assist recombinant interleukin 2 (rIL-2) to enhance successively the percentage of CD3^+ positive cells, maintain the number of CD4^+ positive T cells, promote greatly the percentage of CD8^+ positive T cells among TILs, and reverse the CD4^+/CD8^+ ratio. Such cooperative effects rely on relative specificity of acupoints. It is suggested that MS is beneficial to the growth of TIL both in the aspects of proliferation and phenotypes.

Separation and Expansion of Tumor Infiltrating Lymphocytes of Digestive System in Vitro and Their Cytotoxicity

Primary tumor tissues in the digestive system were harvested form 15 patients. By mincing,enzymatic digestion and gradient density separation, sufficient TILs(>5×106) were obtained from 13 of 15 (88.7%) patients in vitro in the presence of 500 μ/ml of recombinant interleukin-2 and 5% fetal calf serum after one month culture. 92.3% (12/13) of TILs proliferated well in vitro (92.3%). TILs expanded from 102-folds to 103-folds after being cultured for one month. CD25+ cell of the most fresh TILs was more than that of peripheral blood lymphocytes. CD25+ cells of TILs during 4th week of the culture was significantly greater (P<0.01) than that of fresh TILs. CD4+/CD8+ ratio was decreased during four culture weeks because of increase of CD8 cells. By using modified colorimetric MTT assay for measuring activity of TILs against various tumor cells the results showed that cytotoxicity of gastro-intestinal TILs autologous tumor cells is greater than on the other tumor cells.

PD-L1 Expression and Tumor Infiltrating Lymphocytes in Neurofibromatosis Type 1-Related Benign Tumors and Malignant Peripheral Nerve Sheath Tumors:An Implication for Immune Checkpoint Inhibition Therapy

Background Neurofibromatosis type 1(NF1)is an autosomal dominant inherited disorder.It can affect multiple systems of the body and cause severe disfigurement and discomfort in these patients.There are two types of neurofibromas,named cutaneous and plexiform neurofibromas.The latter type may transform into malignant peripheral nerve sheath tumors(MPNSTs).Surgical resection is difficult to perform owing to the complex tissue structure of neurofibromas;therefore,it is necessary to develop novel and effective therapies for the treatment of these tumors.Programmed cell death protein 1(PD-1)/programmed cell death-ligand 1(PD-L1)-related immune checkpoint inhibitors have been proven effective for various cancers,and the positive expression of PD-L1 and tumor-infiltrating lymphocytes(TILs)has been recognized as a biomarker for the response to immune checkpoint therapy.Methods We conducted immunohistochemistry(IHC)staining to detect PD-L1 expression in plexiform neurofibroma and MPNST tissue samples.Reverse transcription-polymerase chain reaction(RT-PCR)and western blotting were performed to detect PD-L1 and PD-1 expression in MPNST cell lines.IHC staining was used to show immune cell infiltration in NF1 and MPNST tissues.Results IHC staining showed PD-L1 positive expression in neurofibromas and MPNST tumor tissues.In addition,qPCR and western blotting showed high expression of PD-L1 in MPNST tumor cells.IHC staining revealed that aberrant T lymphocytes infiltrated the plexiform neurofibroma and MPNST tumor tissues.Conclusion These results indicate that immune checkpoint mechanisms may play a pivotal role in the development of NF1-related tumors,and immune checkpoint inhibitors may be effective for managing neurofibromas and MPNSTs.Combined therapy with other molecular agents may be explored in the future.

A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4^(+)FOXP3^(+) regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

In this study,40 biopsy samples collected from cervical cancer patients at the First Affiliated Hospital of Xi’an Jiaotong University,China,were retrospectively assessed using immunohistochemistry for CD4^(+) and CD8^(+) tumor-infiltrating lymphocytes(TILs)and were analyzed for the expression of FOXP3,OX40,granzyme B(GrB)and perforin(Prf).The proliferating index of the TILs was determined by assessing Ki67 expression.We determined the prognostic value of low and high numbers of TILs on survival by performing Kaplan–Meier analysis using median values as the cut-off points.Except for the number of CD4^(+)FOXP3^(+) regulatory T cells(Tregs)and the CD4/CD8 ratio,none of the CD4^(+),CD8^(+),OX401,GrB^(+) or Prf^(+) TILs were associated with the overall 5-year survival rate.The 5-year survival rate was significantly lower in patients who had a high percentage of Tregs as compared with the those who had a lower percentage(35.3%versus 88.9%,P50.001),while the 5-year survival rate was significantly higher in patients with a high CD4/CD8 ratio as compared with patients who had a low CD4/CD8 ratio(82.4%versus 44.4%,P50.029).When we considered the deaths and surviving cases as separate groups,we found that both the number of CD4^(+) T cells and the CD4/CD8 ratio were significantly lower in patients who died as compared with those who survived(26.33±11.80 versus 47.79±38.18,P=0.023 and 0.60±0.25 versus 1.17±1.02,P=0.019,respectively).In conclusion,decreased proportions of tumor-infiltrating CD4^(+) T cells with high percentages of Tregs and reversed CD4/CD8 ratios were significantly associated with the clinical outcome of patients with cervical carcinoma.

A NEW EXPERIMENTAL AND CLINICAL APPROACH OF COMBINING USAGE OF HIGHLY ACTIVE TUMOR-INFILTRATING LYMPHOCYTES AND HIGHLY SENSITIVE ANTITUMOR DRUGS FOR THE ADVANCED MALIGNANT TUMOR

In recent years, tumor-nfiltrating lymphocytes (TILs) have been reported to be effective for tumors in experimental and clinical research. In order to increase the therapeutical effect, we modified some steps of Rosenberg's approach a. cold digestion with collagenase at 4C for 24 hours; b. sedimentation instead of centrifugation; c. elimination of tumor cells before the cultivation procedure. Compared with the original approach, the proliferation, activity and cytotoxicity of TILs obtained by the modified procedure were much improved. TILs' expansion-old was greater than that with the original approach. Cytotoxicity against rumor cells was more potent. Increased TILs' subsets were CD3 and CD8 cells. Meanwhile, we took tumor cells from tumor tissues to test their in vitro chemosensitivities to different drugs in order to select highly sensitive antitumor drugs for treatment of cases with advanced tumors. According to the design of using highly active TILs and highly sensitive drugs (H & H therapy), preliminary clinical results of 50 cases showed higher response rates than those in treatment with TIL / IL2, LAK / 1L2 and TIL+IL2+CTX. Less toxic side effects were observed in 14 patients.

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.

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8^(+ ) T lymphocytes in human non-small cell lung cancer

T-cell tolerance is an important mechanism for tumor escape,but the molecular pathways involved in T-cell tolerance remain poorly understood.It remains unknown whether the inhibitory immunoreceptor programmed death-1(PD-1)plays a role in conditions of human non-small cell lung cancer(NSCLC).In this study,we detected PD-1 expression on CD81 T cells from healthy control peripheral blood mononuclear cells(PBMCs)and the PBMCs of NSCLC patients as well as NSCLC tissues.Results showed that tumor-infiltrating CD81 T cells had increased PD-1 expression and impaired immune function,including reducing cytokine production capability and impairing capacity to proliferate.Blockade of the PD-1/PD-L1 pathway by the PD-L1-specific antibody partially restored cytokine production and cell proliferation.These data provide direct evidence that the PD-1/PD-L1 pathway is involved in CD81 T-cell dysfunction in NSCLC patients.Moreover,blocking this pathway provides a potential therapy target in lung cancer.

Interleukin-18 and -12 synergistically enhance cytotoxic functions of tumor-infiltrating lymphocytes

Background The role of tumor-infiltrating lymphocytes （TILs） in the immunopathogenesis of individual cancer is not clear and is a challenge for anti-tumor immunotherapy. This study aimed to investigate the effects of interleukin （IL）-18 and -12 on cytotoxic functions of TILs, Methods TILs from postoperative gastric cancer patients were costimulated with IL-18 and IL-12. SGC-7g01 tumor cells were pre-incubated with TILs and subcutaneously injected into BALB/C SCID mice. The function of TILs was evaluated by measuring tumor sizes in tumor-bearing mice, T helper （Th）l （tumor necrosis factor （TNF）-a, interferon （IFN）-y） and Th2 cytokine levels （IL-10 and IL-4） in serum and cytotoxicity of mouse natural killer （NK） and CD8＋ T cells. Results IL-18 and IL-12 synergistically inhibited the growth of SGC-7901 cells in vivo and significantly extended the survival rate of SGC-7901-bearing mice （66.7% vs. 13.7%, P 〈0.01）. Moreover, TILs could promote the secretion of TNF-a and IFN-y （（130.34±7.65） vs. （210.63±12.31） pg/ml, P 〈0.01; （14.23±1.97） vs. （30.52±2.12） pg/ml, P 〈0.01）, and downregulate IL-10 and IL-4 secretion （（103.72±11.21）vs. （61.36±5.41） pg/ml, P=0.021; （49.36±4.67）vs. （28.48±3.86） pg/ml, P=0.024）. Conclusion IL-18 and IL-12 can synergistically enhance cytotoxic functions of TILs from human gastric cancer.

The emergence of tumor-infiltrating lymphocytes in nasopharyngeal carcinoma:Predictive value and immunotherapy implications

The clinical study of nasopharyngeal carcinoma(NPC)often reveals a large number of lymphocytes infiltrating the primary tumor site.As an important part of the tumor microenvironment,tumor-infiltrating lymphocytes(TILs)do not exist alone but as a complex multicellular population with high heterogeneity.TILs play an extremely significant role in the occurrence,development,invasion and metastasis of NPC.The latest research shows that they participate in tumorigenesis and treatment,and the composition,quantity,functional status and distribution of TILs subsets have good predictive value for the prognosis of NPC patients.TILs are an independent prognostic factor for TNM stage and significantly correlated with better prognosis.Additionally,adoptive immunotherapy using anti-tumor TILs has achieved good results in a variety of solid tumors including NPC.This review evaluates recent clinical and preclinical studies of NPC,summarizes the role of TILs in promoting and inhibiting tumor growth,evaluates the predictive value of TILs,and explores the potential benefits of TILs-based immunotherapy in the treatment of NPC.

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.

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.

Density and distribution of lymphocytes in pretherapeutic rectal cancer and response to neoadjuvant therapy

Background:Lymphocytic density in rectal cancer has been reported to be associated with therapeutic response,but the role of the lymphocytic distribution pattern remains to be determined.This study aimed to evaluate the association between the distribution and density of lymphocytes in rectal-cancer tissue with tumor response to neoadjuvant therapy.Methods:We retrospectively analysed 134 patients with rectal cancer receiving neoadjuvant therapy within a prospectively maintained cohort.Pretherapeutic biopsy samples were stained with immunohistochemistry(CD4 and CD8).Densities of intratumoral periglandular lymphocytes(IPLs)and tumor-infiltrating lymphocytes(TILs)were assessed separately.Logistic-regression analysis was used to assess associations of lymphocyte densities with tumor regression grade(TRG),controlling for clinicopathological,molecular,and regimen features.Results:Compared with cases in the lowest quartile of CD8^(+)TILs,those in the highest quartile were significantly associated with better TRG(multivariate odds ratio,0.23;95%confidence interval,0.07 to 0.76;P<0.001).In contrast,CD8^(+)IPLs,CD4^(+)IPLs,and CD4^(+)TILswere not significantly associatedwith TRG(P=0.033,0.156,and 0.170,respectively).Sensitivity analyses detected no interaction between CD8^(+)TILs and regimen of neoadjuvant radiation(Pinteraction=0.831)or chemotherapy(Pinteraction=0.879)on TRG.Conclusions:Our data suggest that CD8^(+)TILs,but not IPLs,are independently associated with response to neoadjuvant therapy,regardless of the regimen of radiation or chemotherapy.

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.