Dataset Information

The tumor microenvironment disarms CD8⁺ T lymphocyte function via a miR-26a-EZH2 axis.

ABSTRACT: One of the most important factors that limit the potency of CD8⁺ cytotoxic T lymphocyte (CTL) responses is the tumor microenvironment (TME). Here, we provide evidence that miR-26a is a negative regulator of CTL function in the TME. Specifically, we identified miR-26a as a crucial suppressor gene in CTLs from the TME, as we found that, miR-26a expression was elevated in CTLs to respond to TME secretome stimulation. CTLs from miR-26a-transgenic mice showed impaired IFN? and granzyme B production in response to their cognate antigen. Conversely, we found that miR-26a inhibition in CTLs could effectively increase the cytotoxicity and suppress tumor growth. Mechanically, we identified EZH2 as a direct target of miR-26a. miR-26a and EZH2 expression were found to be inversely correlated in CTLs, and the inhibition of EZH2 in CTLs impairs CTL function. These functional correlations were validated in a cohort of non-small cell lung cancer patients, indicating that the miR-26a-EZH2 axis is clinically relevant. Our findings suggested that miR-26a silencing as a novel strategy to improve the efficacy of CTL-based cancer immunotherapy.

SUBMITTER: Long H

PROVIDER: S-EPMC5214597 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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The tumor microenvironment disarms CD8<sup>+</sup> T lymphocyte function via a miR-26a-EZH2 axis.

Long Haixia H Xiang Tong T Luo Jing J Li Fei F Lin Regina R Liu Siqi S Jiang Shan S Hu Chunyan C Chen Gang G Wong Elizabeth E Wan Ying Y Li Qi-Jing QJ Zhu Bo B

Oncoimmunology 20161018 12

One of the most important factors that limit the potency of CD8<sup>+</sup> cytotoxic T lymphocyte (CTL) responses is the tumor microenvironment (TME). Here, we provide evidence that miR-26a is a negative regulator of CTL function in the TME. Specifically, we identified miR-26a as a crucial suppressor gene in CTLs from the TME, as we found that, miR-26a expression was elevated in CTLs to respond to TME secretome stimulation. CTLs from miR-26a-transgenic mice showed impaired IFNγ and granzyme B p ...[more]

PMID: 28123882

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Project description:PurposeTo identify CD8+ T lymphocyte-related coexpressed genes that increase CD8+ T lymphocyte proportions in breast cancer and to elucidate the underlying mechanisms among relevant genes in the tumor microenvironment.MethodWe obtained breast cancer expression matrix data and patient phenotype following information from TCGA-BRCA FPKM. Tumor purity, immune score, stromal score, and estimate score were calculated using the estimate package in R. The CD8+ T lymphocyte proportions in each breast carcinoma sample were estimated using the CIBERSORT algorithm. The samples with p < 0.05 were considered to be significant and were taken into the weighted gene coexpression network analysis. Based on the CD8+ T lymphocyte proportion and tumor purity, we generated CD8+ T lymphocyte coexpression networks and selected the most CD8+ T lymphocyte-related module as our interested coexpression modules. We constructed a CD8+ T cell model based on the least absolute shrinkage and selection operator method (LASSO) regression model and robust model and evaluate the prediction ability in different subgroups.ResultsA breast carcinoma CD8+ T lymphocyte proportion coexpression yellow module was determined. The coexpression genes in the yellow module were determined to increase the CD8+ T lymphocyte proportion levels in breast cancer patients. The yellow module was significantly enriched in the antigen presentation process, cellular response to interferon-gamma, and leukocyte proliferation. Subsequently, we generated CD8+ T cell-related genes lasso regression risk model and robust model, and eight genes were taken into the risk model. The risk score showed significant prognostic ability in various subgroups. Expression levels of proteins, encoded by CD74, were lower in the breast carcinoma samples than in normal tissue, suggesting expression differences at both the mRNA and the protein levels.ConclusionThese eight CD8+ T lymphocyte proportion coexpression genes increase CD8+ T lymphocyte in breast cancer by an antigen presentation process. The mechanism might suggest new pathways to improve outcomes in patients who do not benefit from immune therapy.

Project description:BackgroundImmune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. However, most patients with cancer fail to respond clinically. One potential reason is the accumulation of immunosuppressive transforming growth factor β (TGFβ) in the tumor microenvironment (TME). TGFβ drives cancer immune evasion in part by inducing regulatory T cells (Tregs) and limiting CD8+ T cell function. Glycoprotein-A repetitions predominant (GARP) is a cell surface docking receptor for activating latent TGFβ1, TGFβ2 and TGFβ3, with its expression restricted predominantly to effector Tregs, cancer cells, and platelets.MethodsWe investigated the role of GARP in human patients with cancer by analyzing existing large databases. In addition, we generated and humanized an anti-GARP monoclonal antibody and evaluated its antitumor efficacy and underlying mechanisms of action in murine models of cancer.ResultsWe demonstrate that GARP overexpression in human cancers correlates with a tolerogenic TME and poor clinical response to ICB, suggesting GARP blockade may improve cancer immunotherapy. We report on a unique anti-human GARP antibody (named PIIO-1) that specifically binds the ligand-interacting domain of all latent TGFβ isoforms. PIIO-1 lacks recognition of GARP-TGFβ complex on platelets. Using human LRRC32 (encoding GARP) knock-in mice, we find that PIIO-1 does not cause thrombocytopenia; is preferentially distributed in the TME; and exhibits therapeutic efficacy against GARP+ and GARP- cancers, alone or in combination with anti-PD-1 antibody. Mechanistically, PIIO-1 treatment reduces canonical TGFβ signaling in tumor-infiltrating immune cells, prevents T cell exhaustion, and enhances CD8+ T cell migration into the TME in a C-X-C motif chemokine receptor 3 (CXCR3)-dependent manner.ConclusionGARP contributes to multiple aspects of immune resistance in cancer. Anti-human GARP antibody PIIO-1 is an efficacious and safe strategy to block GARP-mediated LTGFβ activation, enhance CD8+ T cell trafficking and functionality in the tumor, and overcome primary resistance to anti-PD-1 ICB. PIIO-1 therefore warrants clinical development as a novel cancer immunotherapeutic.

Project description:PurposeThe aim of this study was to determine whether CD8+ T lymphocyte and its checkpoint-associated module programmed cell death protein 1 (PD-1)/main ligand of PD-1 (PD-L1) pathway impact overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs).Materials and methodsA total of 231 mRCC patients, from 2007 to 2017, treated with sunitinib or sorafenib in Zhongshan Hospital, Fudan University were included in the study analyses. CD8, PD-1, and PD-L1 was assessed by immunohistochemistry on continuous paraffin-embedded slides. Kaplan-Meier method and COX regression model were applied in the survival analyses.ResultsBaseline characteristics were comparable between the training (n=118) and validation (n=113) sets. Patients with high CD8+ T lymphocytes infiltration and low PD-1 expression had longer survival in both sets (P=0.0106 and P=0.0047 in training set, P=0.0291 and P=0.0011 in validation set, respectively). However, survival stratified by PD-L1 was only insignificant or marginally significant. Multivariable analyses verified that CD8+ T lymphocytes, together with PD-1, but not tumor infiltrating mononuclear cells or tumor cells PD-L1, were independent prognostic factors (training set [HR 3.202, 95% CI 1.433-7.153, P=0.011] and validation set [HR 4.012, 95% CI 2.354-6.838, P<0.001]). Subsequent analysis revealed that the PD-1 high/CD8 low group had shorter survival (16 months) than PD-1 low/CD8 high group (51 months, P<0.0001). Combining the International Metastatic Renal Cancer Database Consortium system with the PD-1/CD8 model exhibited much better accuracy for the prediction of OS.ConclusionOur findings suggest that abundant CD8+ T cells are significantly associated with longer OS in mRCC patients treated with TKIs. The most influential checkpoint-associated molecule, PD-1, assisted CD8+ T cell-stratified patients and could be used as a better predictive and prognostic factor for the mRCC patients.

Dataset Information

The tumor microenvironment disarms CD8⁺ T lymphocyte function via a miR-26a-EZH2 axis.

Publications

The tumor microenvironment disarms CD8<sup>+</sup> T lymphocyte function via a miR-26a-EZH2 axis.

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Dataset Information

The tumor microenvironment disarms CD8+ T lymphocyte function via a miR-26a-EZH2 axis.

Publications

The tumor microenvironment disarms CD8<sup>+</sup> T lymphocyte function via a miR-26a-EZH2 axis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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The tumor microenvironment disarms CD8⁺ T lymphocyte function via a miR-26a-EZH2 axis.