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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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			Action	DRS
	SRR24921247.fastq.gz	Fastqsanger.gz
	SRR24921248.fastq.gz	Fastqsanger.gz

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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 I

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 | GSE234974 | GEO

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

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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

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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

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

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

Project description:CD8+ T cells must persist and function in diverse tumor microenvironments to exert their effects. Thus, understanding common underlying expression programs could better inform the next generation of immunotherapies. We apply a generalizable matrix factorization algorithm that recovers both shared and context-specific expression programs from diverse datasets to a single-cell RNA sequencing (scRNA-seq) compendium of 33,161 CD8+ T cells from 132 patients with seven human cancers. Our meta-single-cell analyses uncover a pan-cancer T cell dysfunction program that predicts clinical non-response to checkpoint blockade in melanoma and highlights CXCR6 as a pan-cancer marker of chronically activated T cells. Cxcr6 is trans-activated by AP-1 and repressed by TCF1. Using mouse models, we show that Cxcr6 deletion in CD8+ T cells increases apoptosis of PD1+TIM3+ cells, dampens CD28 signaling, and compromises tumor growth control. Our study uncovers a TCF1:CXCR6 axis that counterbalances PD1-mediated suppression of CD8+ cell responses and is essential for effective anti-tumor immunity.

| S-EPMC11293343 | biostudies-literature

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

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.

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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

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