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Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity II

ABSTRACT: Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity II

PROVIDER: PRJNA983825 | ENA |

REPOSITORIES: ENA

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Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity III

Project description:Cytotoxic CD8+ T cells need to persist and function in diverse tumor microenvironments to exert their effects. Here, we developed Generalizable Matrix Decomposition Framework (GMDF), a matrix factorization algorithm that recovers both shared and tumor type-specific transcriptional programs from diverse data sets, and applied it to a scRNA-seq compendium of 38,852 CD8+ T cells from 141 patients spanning nine different human cancers. Our meta-single-cell analyses uncovered a pan-cancer T cell dysfunction program that was predictive of clinical responses to checkpoint blockade in melanoma and highlighted CXCR6 as a pan-cancer marker of chronically activated T cells. CXCR6 transcription was activated by AP-1 factors and repressed by TCF1. In mouse models, CXCR6 expression increased with tumor progression and upon checkpoint blockade. CXCR6 deletion in CD8+ T cells increased apoptosis of PD1+Tim3+ cells and compromised tumor growth control due to suppressed expression of survival factors and CD28 co-stimulation, revealing a role for CXCR6 in opposing PD1-mediated suppression of CD28 signaling. Our application of GMDF led us to discover a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8+ cell responses and is essential for effective anti-tumor immunity.

2024-07-02 | GSE234976 | GEO

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity II

2024-07-02 | GSE234975 | GEO

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity I

2024-07-02 | GSE234974 | GEO

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity

Project description:Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity

| PRJNA983827 | ENA

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity I

Project description:Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity I

| PRJNA983823 | ENA

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity III

Project description:Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity III

| PRJNA983831 | ENA

CD28 Co-stimulation Drives Tumor-Infiltrating T Cell Glycolysis to Promote Inflammation

Project description:Metabolic reprogramming dictates the fate and function of stimulated T cells, yet these pathways can be suppressed in T cells subjected to unique microenvironments, such as in a tumor. We previously showed that glycolytic and mitochondrial adaptations directly contribute to reduced effector functions of Renal Cell Carcinoma (RCC) CD8 tumor infiltrating lymphocytes (TIL). Here we define the role of these metabolic pathways in the activation and effector functions of RCC CD8 TIL. CD28 co-stimulation plays a key role to augment T cell activation and metabolism and is antagonized by inhibitory and checkpoint immunotherapy receptors CTLA4 and PD-1. While RCC CD8 TIL activated poorly when stimulated through the T cell receptor alone, addition of CD28 co-stimulation greatly enhanced activation, function, and proliferation. CD28 co-stimulation reprogrammed RCC CD8 TIL metabolism with increased glycolysis and mitochondrial oxidative metabolism, in part through upregulation of GLUT3. Mitochondria also became more fused, with higher membrane potential and overall mass. These phenotypes were dependent on glucose metabolism, as the glycolytic inhibitor 2-deoxyglucose both prevented changes to mitochondria and suppressed RCC CD8 TIL activation and function. These data show that CD28 co-stimulation can restore RCC CD8 TIL metabolism and function through rescue of T cell glycolysis that supports mitochondrial mass and activity.

2020-08-10 | GSE151669 | GEO

Pan-cancer mapping of single CD8+ T cell profiles reveals a TCF1:CXCR6 axis regulating CD28 co-stimulation and anti-tumor immunity

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-07-02 | GSE234977 | GEO

Expression profile of CXCR6 Hi T cells or CXCR6 Lo helper T cells in CD45Rb Hi tranfer model mice

Project description:To identify the role of chemokine receptor in inflammation of colon, we isolated CD3+CD4+ helper T cells harboring CXCR6 from colonic lamina propria of mice We used microarrays to identify the differentially expressed genes between CXCR6Hi Tcells and CXCR6Lo Tcells CXCR6 Hi or CXCR6 Lo T cells were isolated from colonic lamina propria for RNA extraction and hybridization on Affymetrix microarrays.

2013-04-09 | E-GEOD-45881 | biostudies-arrayexpress

PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15

Project description:Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8+ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8+ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1-induced human T-cell reinvigoration using tumor-infiltrating CD8+ T cells (CD8+ TILs) obtained from non-small cell lung cancer patients. Single cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8+ TILs. Furthermore, we found that human CD28+CD8+, but not CD28–CD8+ TILs, responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 co-stimulation in human CD8+ TILs is dispensable for PD-1 blockade-induced reinvigoration, and loss of CD28 expression rather serve as a marker of anti-PD-1-unresponsive CD8+ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28–PD-1+CD8+ TILs exhibited characteristics of terminally exhausted CD8+ T cells with low TCF1 expression. Notably, CD28–PD-1+CD8+ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced proliferation of CD28–PD-1+CD8+ TILs as well as CD28+PD-1+CD8+ TILs. Taken together, we demonstrate loss of CD28 expression as a marker of PD-1 blockade-unresponsive human CD8+ TILs with TCF1– signature and provide mechanistic insights into combining IL-15 with anti-PD-1.

2020-05-01 | GSE145896 | GEO

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