Tumor-infiltrating T Lymphocytes Research Articles

Identifying signatures of EV secretion in metastatic breast cancer through functional single-cell profiling

Extracellular vesicles (EVs) regulate the tumor microenvironment by facilitating transport of biomolecules. Despite extensive investigation, heterogeneity in EV secretion among cancer cells and the mechanisms that support EV secretion are not well characterized. We developed an integrated method to identify individual cells with differences in EV secretion and performed linked single-cell RNA-sequencing on cloned single cells from the metastatic breast cancer cells. Differential gene expression analyses identified a four-gene signature of breast cancer EV secretion: HSP90AA1, HSPH1, EIF5, and DIAPH3. We functionally validated this gene signature by testing it across cell lines with different metastatic potential invitro. Analysis of the TCGA and METABRIC datasets showed that this signature is associated with poor survival, invasive breast cancer types, and poor CD8+ Tcell infiltration in human tumors. We anticipate that our method for directly identifying the molecular determinants of EV secretion will have broad applications across cell types and diseases.

CD83 expression characterizes precursor exhausted T cell population

T cell exhaustion is a main obstacle against effective cancer immunotherapy. Exhausted T cells include a subpopulation that maintains proliferative capacity, referred to as precursor exhausted T cells (TPEX). While functionally distinct and important for antitumor immunity, TPEX possess some overlapping phenotypic features with the other T-cell subsets within the heterogeneous tumor-infiltrating T-lymphocytes (TIL). Here we explore surface marker profiles unique to TPEX using the tumor models treated by chimeric antigen receptor (CAR)-engineered T cells. We find that CD83 is predominantly expressed in the CCR7+PD1+ intratumoral CAR-T cells compared with the CCR7-PD1+ (terminally differentiated) and CAR-negative (bystander) T cells. The CD83+CCR7+ CAR-T cells exhibit superior antigen-induced proliferation and IL-2 production compared with the CD83- T cells. Moreover, we confirm selective expression of CD83 in the CCR7+PD1+ T-cell population in primary TIL samples. Our findings identify CD83 as a marker to discriminate TPEX from terminally exhausted and bystander TIL.

Low-dose metronomic gemcitabine pretreatments overcome the resistance of breast cancer to immune checkpoint therapy.

Aims: Immunotherapy has revolutionized cancer management. However, response to immunotherapy is heterogeneous. Thus, strategies to improve antitumor immune responses in resistant tumors, such as breast cancer, are urgently needed. Methods: Established murine tumors were treated with anti-CTLA4 or anti-PD-1 alone or combined with metronomic gemcitabine (met-GEM). Tumor vascular function, immune cell tumor infiltration and gene transcription were determined. Results: Low-dose met-GEM (2mg/kg) treatments improved tumor vessel perfusion and increased tumor-infiltrating T cells. Notably, low-dose met-GEM pretreatments converted resistant tumors to respond to immunotherapy. Moreover, combined therapy reduced tumor vessel density, improved tumor vessel perfusion, increased T-cell tumor infiltration and upregulated the expression of some anticancer genes. Conclusion: Low-dose met-GEM pretreatment reconditioned the tumor immune microenvironment and improved immunotherapy efficacy in murine breast cancer.

Profiling specific cell populations within the inflammatory tumor microenvironment by oscillating-gradient diffusion-weighted MRI

BackgroundThe inflammatory tumor microenvironment (TME) is formed by various immune cells, being closely associated with tumorigenesis. Especially, the interaction between tumor-infiltrating T-cells and macrophages has a crucial impact on tumor...

SN-38, an active metabolite of irinotecan, enhances anti-PD-1 treatment efficacy in head and neck squamous cell carcinoma.

Anti-programmed cell death 1 (anti-PD-1) therapy shows definite but modest activity in patients with advanced/metastatic head and neck squamous cell carcinoma (HNSCC). Preliminary evidence suggests that SN-38, an activated form of irinotecan that increases expression of the transcription factor FoxO3a, can suppress programmed cell death ligand-1 (PD-L1) expression in breast and ovarian tumor models. We analyzed the SN-38-mediated activation of natural killer cells in vitro and explored the efficacy of SN-38 in combination with anti-PD-1 for treatment in vivo. In vitro, SN-38 enhanced the expression of FoxO3a and reduced the expression of c-Myc and PD-L1 dose-dependently in tumor cells. Low-dose SN-38 increased interferon-γ secretion by NK cells and promoted NK cell-mediated cytotoxicity in tumor cells. In vivo studies revealed that at non-cytotoxic drug concentrations, SN-38 significantly enhanced anti-PD-1 activity in suppressing murine tumor growth. We found increased NK cell and CD8+ T-cell infiltration in post-treatment tumors. RNA-seq analysis indicated that SN-38 increased the enrichment of immune cells and biological function genes related to the immune responses. SN-38 is a potentially beneficial adjunct to checkpoint inhibitor therapy in HNSCC. Further studies exploring its mechanism of action and possible applications are necessary. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Generation of colon cancer–derived tumor-infiltrating T cells (TILs) for adoptive cell therapy

Adoptive cell therapy (ACT) using specific immune cells and stem cells has emerged as a promising treatment option that could complement traditional cancer therapies in the future. In particular, tumor-infiltrating lymphocytes (TILs) have been shown to be effective against solid tumors in various clinical trials. Despite the enormous disease burden and large number of premature deaths caused by colorectal cancer (CRC), studies on TILs isolated from tumor tissue of patients with CRC are still rare. To date, studies on ACT often lack controlled and comparable expansion processes as well as selected ACT-relevant T-cell populations. We describe a procedure for generating patient-specific TILs, which are prerequisites for clinical trials of ACT in CRC. The manufacturing and characteristics of these TILs differ in important modalities from TILs commonly used for this therapeutic approach. Tumor tissue samples were obtained from 12 patients undergoing surgery for primary CRC, predominantly with low microsatellite instability (pMMR-MSI-L). Tumors in the resected specimens were examined pathologically, and an approved volume of tumor tissue was transferred to a disposable perfusion bioreactor. Tissue samples were subjected to an automatically controlled and highly reproducible cultivation process in a GMP-conform, closed perfusion bioreactor system using starting medium containing interleukin-2 and interleukin-12. Outgrowth of TIL from tissue samples was initiated by short-term supplementation with a specific activation cocktail. During subsequent expansion, TILs were grown in interleukin-2–enriched medium. Expansion of TILs in a low-scaled, two-phase process in the Zellwerk ZRP bioreactor under hyperoxic conditions resulted in a number of approximately 2 × 109 cells. The expanded TILs consisted mainly (73%) of the ACT-relevant CD3+/CD8+ effector memory phenotype (CD45RO+/CCR7−). TILs harvested under these conditions exhibited high functional potential, which was confirmed upon nonspecific stimulation (interferon-γ, tumor necrosis factor-α cytokine assay)

Artificial intelligence (AI) -powered spatial analysis of tumor-infiltrating lymphocytes (TIL) for prediction of prognosis in stage II-III resectable colon cancer.

211 Background: T-cell infiltration in tumors and the surrounding stroma has been suggested as an important prognostic marker in colorectal cancer, but assessment usually requires additional tissue processing and interpretational efforts. The aim of this study is to assess the clinical significance of AI-powered spatial TIL analysis using only a hematoxylin and eosin (H&E)-stained whole-slide image (WSI) for the prediction of prognosis in stage II-III colon cancer patients treated with surgery and adjuvant chemotherapy. Methods: H&E-stained WSI of primary tumors and clinical data were collected retrospectively from stage II or III colon cancer patients treated with curative surgery and adjuvant chemotherapy at Seoul National University Bundang Hospital (Seongnam, Korea) between 2009 and 2012. For spatial TIL analysis, we used Lunit SCOPE IO, an AI-powered H&E WSI analyzer, which identifies and quantifies TIL within cancer or stroma area from a representative H&E-stained WSI. Intratumoral (iTIL) and stromal TIL (sTIL) densities were defined as the number of TILs in the intratumoral area (/mm2) and the surrounding stroma (/mm2), respectively. Results: A total of 289 patients were included in this analysis. During the follow-up period (median 99.6 months, 95% confidence interval [CI] 95.8 - 103.5), 28 (9.7%) recurrences were observed. The median iTIL and sTIL densities in all patients were 44.4 (/mm2, interquartile range [IQR] 28.4 – 71.7) and 878.0 (/mm2, IQR 554.9 – 1209.6), and showed a modest positive correlation (Pearson’s r = 0.349, p < 0.001). Patients having tumors with high microsatellite instability (MSI-H) status were more likely to have higher iTIL densities (mean iTIL 161.5/mm2 in MSI-H vs. 58.9/mm2 in MSI-L/MSS, p = 0.024), and patients with stage II disease (vs. stage III, iTIL and sTIL, p = 0.046 and 0.049, respectively) or without perineural invasion (vs. invasion (+), iTIL, p = 0.001) were also more likely to have higher mean iTIL and/or sTIL densities. Analyzing the iTIL, sTIL densities in association to clinical outcomes, the patients with confirmed recurrences had significantly lower mean sTIL density compared to those without recurrences (630.2/mm2 in recurrence (+) vs. 1021.3/mm2 in recurrence (-), p < 0.001). Comparing the risk of recurrence using the quartile cutoffs, the patients having either sTIL or iTIL densities in the lowest quartile were more likely to recur (unadjusted hazard ratio[HR]s of lowest quartile vs. others in sTIL, 2.77 [95% CI 1.32 - 5.82], p = 0.009; iTIL, 2.68 [95% CI 1.28 – 5.64], p = 0.009). Patients having both sTIL and iTIL in the lowest quartile (N=31) had the highest risk of recurrence, exhibiting a recurrence rate at 3 years of 26.1% (HR 4.30, 95% CI 1.94-9.51, p <0.001). Conclusions: AI-powered TIL analysis can provide prognostic information for stage II-III colon cancer in a practical manner.

Tissue-Resident Memory T Cells in Pancreatic Ductal Adenocarcinoma Coexpress PD-1 and TIGIT and Functional Inhibition Is Reversible by Dual Antibody Blockade.

Pancreatic ductal adenocarcinoma (PDAC) has a poor clinical outlook. Responses to immune checkpoint blockade are suboptimal and a much more detailed understanding of the tumor immune microenvironment is needed if this situation is to be improved. Here, we characterized tumor-infiltrating T-cell populations in patients with PDAC using cytometry by time of flight (CyTOF) and single-cell RNA sequencing. T cells were the predominant immune cell subset observed within tumors. Over 30% of CD4+ T cells expressed a CCR6+CD161+ Th17 phenotype and 17% displayed an activated regulatory T-cell profile. Large populations of CD8+ tissue-resident memory (TRM) T cells were also present and expressed high levels of programmed cell death protein 1 (PD-1) and TIGIT. A population of putative tumor-reactive CD103+CD39+ T cells was also observed within the CD8+ tumor-infiltrating lymphocytes population. The expression of PD-1 ligands was limited largely to hemopoietic cells whilst TIGIT ligands were expressed widely within the tumor microenvironment. Programmed death-ligand 1 and CD155 were expressed within the T-cell area of ectopic lymphoid structures and colocalized with PD-1+TIGIT+ CD8+ T cells. Combinatorial anti-PD-1 and TIGIT blockade enhanced IFNγ secretion and proliferation of T cells in the presence of PD-1 and TIGIT ligands. As such, we showed that the PDAC microenvironment is characterized by the presence of substantial populations of TRM cells with an exhausted PD-1+TIGIT+ phenotype where dual checkpoint receptor blockade represents a promising avenue for future immunotherapy.

Role of FABP5 in T Cell Lipid Metabolism and Function in the Tumor Microenvironment.

To evade immune surveillance, tumors develop a hostile microenvironment that inhibits anti-tumor immunity. Recent immunotherapy breakthroughs that target the reinvigoration of tumor-infiltrating T lymphocytes (TIL) have led to unprecedented success in treating some cancers that are resistant to conventional therapy, suggesting that T cells play a pivotal role in anti-tumor immunity. In the hostile tumor microenvironment (TME), activated T cells are known to mainly rely on aerobic glycolysis to facilitate their proliferation and anti-tumor function. However, TILs usually exhibit an exhausted phenotype and impaired anti-tumor activity due to the limited availability of key nutrients (e.g., glucose) in the TME. Given that different T cell subsets have unique metabolic pathways which determine their effector function, this review introduces our current understanding of T cell development, activation signals and metabolic pathways. Moreover, emerging evidence suggests that fatty acid binding protein 5 (FABP5) expression in T cells regulates T cell lipid metabolism and function. We highlight how FABP5 regulates fatty acid uptake and oxidation, thus shaping the survival and function of different T cell subsets in the TME.

Fecal and Tissue Microbiota Are Associated with Tumor T-Cell Infiltration and Mesenteric Lymph Node Involvement in Colorectal Cancer.

Colorectal cancer (CRC) is associated with alterations of the fecal and tissue-associated microbiome. Preclinical models support a pathogenic role of the microbiome in CRC, including in promoting metastasis and modulating antitumor immune responses. To investigate whether the microbiome is associated with lymph node metastasis and T cell infiltration in human CRC, we performed 16S rRNA gene sequencing of feces, tumor core, tumor surface, and healthy adjacent tissue collected from 34 CRC patients undergoing surgery (28 fecal samples and 39 tissue samples). Tissue microbiome profiles-including increased Fusobacterium-were significantly associated with mesenteric lymph node (MLN) involvement. Fecal microbes were also associated with MLN involvement and accurately classified CRC patients into those with or without MLN involvement. Tumor T cell infiltration was assessed by immunohistochemical staining of CD3 and CD8 in tumor tissue sections. Tumor core microbiota, including members of the Blautia and Faecalibacterium genera, were significantly associated with tumor T cell infiltration. Abundance of specific fecal microbes including a member of the Roseburia genus predicted high vs. low total and cytotoxic T cell infiltration in random forests classifiers. These findings support a link between the microbiome and antitumor immune responses that may influence prognosis of locally advanced CRC.

Mutant KRAS Drives Immune Evasion by Sensitizing Cytotoxic T-Cells to Activation-Induced Cell Death in Colorectal Cancer.

The roles of oncogenic KRAS in tumor immune evasion remain poorly understood. Here, mutant KRAS is identified as a key driver of tumor immune evasion in colorectal cancer (CRC). In human CRC specimens, a significant reduction in cytotoxic CD8+ T-cell tumor infiltration is found in patients with mutant versus wild type KRAS. This phenomenon is confirmed by preclinical models of CRC, and further study showed KRAS mutant tumors exhibited poor response to anti-PD-1 and adoptive T-cell therapies. Mechanistic analysis revealed lactic acid derived from mutant KRAS-expressing tumor cells sensitized tumor-specific cytotoxic CD8+ T-cells to activation-induced cell death via NF-κB inactivation; this may underlie the inverse association between intratumoral cytotoxic CD8+ T-cells and KRAS mutation. Importantly, KRAS mutated tumor resistance to immunotherapies can be overcome by inhibiting KRAS or blocking lactic acid production. Together, this work suggests the KRAS-mediated immune program is an exploitable therapeutic approach for the treatment of patients with KRAS mutant CRC.

Systemic Inflammatory Biomarkers Predict Survival of Patients Treated With Tyrosine Kinase Inhibitors for Metastatic Renal Cell Carcinoma.

We aimed to retrospectively investigate whether the neutrophil to lymphocyte ratio (NLR) and the monocyte to lymphocyte ratio (MLR) can predict the prognosis of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib or sorafenib. We retrospectively identified 210 patients with mRCC treated with sunitinib or sorafenib from 2007 to 2017 at Fudan University- and Hexi University-affiliated hospitals. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. Multivariate regression analysis was used to evaluate predictors of PFS and OS. Low NLR (<2.85) and MLR (<.30) were strongly associated with increased PFS and OS. Multivariable analyses verified that the NLR and MLR were both independent prognostic factors. Additionally, the NLR was negatively correlated with CD8+ and CD4+ T-cell infiltration in tumors. In patients with mRCC treated with sunitinib and sorafenib, an NLR <2.85 and MLR <.30 was associated with superior PFS and OS, which may be related to the reduced lymphocytic infiltration of tumors.

Prognostic value of tumor-infiltrating T-lymphocytes density in the therapeutic response to initial platinum-based chemotherapy in patients with non-small cell lung cancer

Background/Aim. The fact that lung carcinomas, like other solid tumors, can be immunogenic may have a substantial prognostic value in non-small cell lung cancer (NSCLC). Specific cytotoxic T-lymphocytes (CTL) can be demonstrated in most patients with primary tumors of different histological types. Two main groups of T-lymphocytes participate in the coupled recognition of tumor-specific antigens ? CTL (CD8+) and helper T-lymphocytes (CD4+). The aim of the study was to assess the relationship between the tumor infiltration of T-lymphocytes and the therapeutic response to initial chemotherapy. Methods. Data were obtained from patients with NSCLC whose therapeutic response after four cycles of initial platinum-based chemotherapy was observed in relation to the density of tumor-infiltrating T-lymphocytes (CD4+ and CD8+) in small tumor biopsy samples. The therapeutic response was assessed in line with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 therapeutic response evaluation system. Based on the expected therapeutic response, the patients were divided into three groups: favorable therapeutic response patients (complete and partial regression), stable disease patients, and disease progression patients. To assess the density of CD4+ and CD8+ T-lymphocytes, the number of lymphocytes was determined at ?200 magnification (1.1 mm2). Three visual fields with the densest lymphocyte infiltrate were selected for counting, and the values of all individual fields were added up. Based on the mean value, the samples were classified into the following groups: score 0, score 1, score 2, and score 3. During statistical data processing, low infiltration density combined score 0 and score 1 groups, and high infiltration density combined score 2 and score 3 groups. Based on the collected data, a database was created in SPSS 22.0 software and used for further statistical analysis. Statistical analysis of the data included descriptive and analytical statistics methods. Results. There was no significant difference in the distribution of CD4+ T-lymphocytes and CD8+ T-lymphocytes in the epithelial component of the tumor between patients with a different therapeutic response (?2 = 2.977; p = 0.226 and ?2 = 1.329; p = 0.515, respectively). There was no significant influence of the infiltration density of CD4+ T-lymphocytes and CD8+ T-lymphocytes in the stromal component of the tumor on the therapeutic response (?2 = 0.606; p = 0.739 and ?2 = 5.167; p = 0.076, respectively). Conclusion. The research did not prove that patients with a high level of tumor-infiltrating CD4+ and CD8+ T-lymphocytes in the epithelial and stromal component of the NSCLC had a better therapeutic response to standard initial chemotherapy.

Association of MARCH7 with tumor progression and T-cell infiltration in esophageal cancer

MARCH7 is an E3 ubiquitin ligase known to regulate neuronal development,T-cell proliferation, and cell and tissue differentiation. But, the altered expression of MARCH7 has been observed in various malignancies. Herein, the cellular localization and role of MARCH7have been elucidated in esophageal squamous cell carcinoma (ESCC), the information regarding which is currently limited.To check the expression of MARCH7 and its correlation with immune cells infiltration in ESCC, immunohistochemical analysis was performed. RNAi approach was used to investigate the role of MARCH7 in esophagealcancer cells.Interestingly, we found a significantly higher expression of MARCH7 protein in 84% of ESCC tissues than in distant matched non-malignant tissues (p ≤ 0.001). In addition to this, immunohistochemistry resultshave showna negative correlation between MARCH7 protein expression and tumor-infiltrating immune cells such as CD8 + T cells (r = -0.633, p = 0.001) and PD1 + T cells (r = -0.560, p = 0.005). Furthermore, MARCH7 silencing inhibited the ESCC cell growth and reduced the clonogenic and invasion/migration potential of ESCC cells. MARCH7 silencing also significantly increased E-cadherin protein levels in ESCC cells relative to those in negative controlcells (p < 0.05). Thus, MARCH7 is oncogenic and might have a possible role in esophageal carcinogenesis. Moreover, E-cadherin may be a downstream target of MARCH7 in ESCC.

Celecoxib promotes the efficacy of STING-targeted therapy by increasing antitumor CD8+ T-cell functions via modulating glucose metabolism of CD11b+ Ly6G+ cells.

Recent studies have shown that activation of the cGAS-STING pathway is a key process in antitumor immune responses and various kinds of STING agonists have been developed for cancer immunotherapy. Despite promising preclinical studies, preliminary clinical results have shown only a modest effect of STING agonists. There is therefore a need to develop more effective treatment strategies. Based on previous observations that COX-2 is frequently overexpressed not only in a variety of cancers but also in tumor myeloid cells and that it suppresses antitumor immunity and promotes tumor survival by producing PGE2, we investigated the antitumor effects of combination therapy with a STING agonist cGAMP and the selective COX-2 inhibitor celecoxib in mouse models. Combination treatment with cGAMP and celecoxib inhibited tumor growth compared with either monotherapy, and the combination therapy induced both local and systemic antitumor immunity. cGAMP treatment decreased PD-1 expression on tumor-infiltrating T-cells and enhanced T-cell activation in tumor-draining lymph nodes regardless of the presence of celecoxib. Meanwhile, although celecoxib treatment did not alter the frequency of CD4+ CD25+ Foxp3+ regulatory T-cells, it enhanced the expression of costimulatory molecules and glycolysis-associated genes in tumor-infiltrating CD11b+ Ly6G+ cells. Moreover, we also found that celecoxib decreased lactate efflux and increased the frequency of IFN-γ- and TNF-α-producing CD8+ T-cells in the tumor microenvironment. Taken together, our findings suggest that combined treatment with celecoxib may be an effective strategy to improve the antitumor efficacy of STING agonists.

High-Dose Intermittent Treatment with the Multikinase Inhibitor Sunitinib Leads to High Intra-Tumor Drug Exposure in Patients with Advanced Solid Tumors

Patients with advanced cancer refractory to standard treatment were treated with sunitinib at a dose of 300 mg once every week (Q1W) or 700 mg once every two weeks (Q2W). Tumor, skin and plasma concentrations were measured and immunohistochemical staining for tumor cell proliferation (TCP), microvessel density (MVD) and T-cell infiltration was performed on tumor biopsies before and after 17 days of treatment. Oral administration of 300 mg sunitinib Q1W or 700 mg Q2W resulted in 19-fold (range 5-35×) and 37-fold higher (range 10-88×) tumor drug concentrations compared to parallel maximum plasma drug concentrations, respectively. Patients with higher tumor sunitinib concentrations had favorable progression-free and overall survival than those with lower concentrations (p = 0.046 and 0.024, respectively). In addition, immunohistochemistry of tumor biopsies revealed an induction of T-cell infiltration upon treatment. These findings provide pharmacological and biological insights in the clinical benefit from high-dose intermittent sunitinib treatment. It emphasizes the potential benefit from reaching higher tumor drug concentrations and the value of measuring TKI tumor- over plasma-concentrations. The finding that reaching higher tumor drug concentrations provides most clinical benefit in patients with treatment refractory malignancies indicates that the inhibitory potency of sunitinib may be enforced by a high-dose intermittent treatment schedule. These results provide proof of concept for testing other clinically available multitargeted tyrosine kinase inhibitors in a high-dose intermittent treatment schedule.

T-Cell Mediated Immunity in Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine characteristics. MCC can originate from either the presence of MCC polyomavirus (MCPyV) DNA or chronic ultraviolet (UV) exposure that can cause DNA mutations. MCC is predominant in sun-exposed regions of the body and can metastasize to regional lymph nodes, liver, lungs, bone, and brain. Older, light-skinned individuals with a history of significant sun exposure are at the highest risk. Previous studies have shown that tumors containing a high number of tumor-infiltrating T-cells have favorable survival, even in the absence of MCPyV DNA, suggesting that MCPyV infection enhances T-cell infiltration. However, other factors may also play a role in the host antitumor response. Herein, we review the impact of tumor infiltrating lymphocytes (TILs), mainly the CD4+, CD8+, and regulatory T-cell (Tregs) responses on the course of MCC, including their role in initiating MCPyV-specific immune responses. Furthermore, potential research avenues related to T-cell biology in MCC, as well as relevant immunotherapies are discussed.

13P Tumor-infiltrating CD8/CD103/TIM-3-expressing lymphocytes in epithelial ovarian cancer co-express CXCL13 and associate with improved survival

Reactivation of tumor-infiltrating T lymphocytes (TILs) with immune checkpoint inhibitors or co-stimulators has proven to be an effective anti-cancer strategy for a broad range of malignancies. However, epithelial ovarian cancer (EOC) remains largely refractory to current T cell-targeting immunotherapeutics. Therefore, identification of novel immune checkpoint targets and biomarkers with prognostic value for EOC is warranted. We here identified a TIM-3/CXCL13-positive tissue-resident memory (CD8/CD103-positive) T cell (Trm) population in EOC.

IRF2 integrates inflammatory signals to balance T cell exhaustion

The transcription factor interferon regulatory factor 2 (IRF2) translates interferon signaling to regulate Tcells. In this issue of Immunity, Lukhele etal. identify IRF2 in tumor-infiltrating Tcells as a sensor for extrinsic signals that drives an exhaustion program.

PP4 inhibition sensitizes ovarian cancer to NK cell-mediated cytotoxicity via STAT1 activation and inflammatory signaling

BackgroundIncreased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in ovarian...