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The Transcription Factor IRF4 Determines the Anti-Tumor Immunity of CD8+ T cells

ABSTRACT: The Transcription Factor IRF4 Determines the Anti-Tumor Immunity of CD8+ T cells

PROVIDER: PRJNA946670 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23921100_1.fastq.gz	Fastqsanger.gz
	SRR23921100_2.fastq.gz	Fastqsanger.gz
	SRR23921101_1.fastq.gz	Fastqsanger.gz
	SRR23921101_2.fastq.gz	Fastqsanger.gz
	SRR23921102_1.fastq.gz	Fastqsanger.gz

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The Transcription Factor IRF4 Determines the Anti-Tumor Immunity of CD8+ T cells

Project description:Four TIL populations from B16-F10 melanoma were analyzed by scRNA-seq, including adoptively transterred anti-tumor CD8+ Pmel-1 T cells that were transduced with IRF4 (sample 1, IRF4_Pmel) or GFP control (Sample 3, Ctrl_Pmel), and CD45+ endogenous TILs from either the IRF4 group (Sample 2, IRF4_TILs) or Ctrl group (Sample 4, Ctrl_TILS).

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Autophagy Suppresses CD8+ T cell Anti-tumour Immunity

Project description:Autophagy Suppresses CD8+ T cell Anti-tumour Immunity

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Genome-wide fitness gene identification reveals Roquin as a potent suppressor of CD8 T cell expansion and anti-tumor immunity

Project description:Robust expansion of adoptively transferred T cells is a prerequisite for effective cancer immunotherapy, but how many genes in the genome modulate T cell expansion remains unknown. Here, we performed in vivo and in vitro CRISPR screens to systematically identify genes influencing CD8 T cell expansion. In the mouse genome, ~ 2,600 and ~ 1,500 genes were required for optimal CD8 T cell expansion in vivo and in vitro, respectively. In vivo-specific CD8 T cell essential genes were enriched in metabolic pathways including mitochondrial metabolism. The strongest repressor of CD8 T cell expansion was Roquin, ablation of which drastically boosted T cell proliferation by enhancing cell cycle progression and upregulation of IRF4. Roquin-deficiency or IRF4 overexpression potently enhanced anti-tumor immunity. These data provide a functional catalog of CD8 T cell fitness genes, and suggest targeting Roquin-IRF4 axis is an effective strategy to enhance efficacy of adoptive transfer therapy for cancer.

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The transcription factor IRF4 determines the anti-tumor immunity of CD8<sup>+</sup> T cells.

Project description:Understanding the factors that regulate T cell infiltration and functional states in solid tumors is crucial for advancing cancer immunotherapies. Here, we discovered that the expression of interferon regulatory factor 4 (IRF4) was a critical T cell intrinsic requirement for effective anti-tumor immunity. Mice with T-cell-specific ablation of IRF4 showed significantly reduced T cell tumor infiltration and function, resulting in accelerated growth of subcutaneous syngeneic tumors and allowing the growth of allogeneic tumors. Additionally, engineered overexpression of IRF4 in anti-tumor CD8+ T cells that were adoptively transferred significantly promoted their tumor infiltration and transition from a naive/memory-like cell state into effector T cell states. As a result, IRF4-engineered anti-tumor T cells exhibited significantly improved anti-tumor efficacy, and inhibited tumor growth either alone or in combination with PD-L1 blockade. These findings identify IRF4 as a crucial cell-intrinsic driver of T cell infiltration and function in tumors, emphasizing the potential of IRF4-engineering as an immunotherapeutic approach.

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Project description:Here we demonstrate that inactivation of the essential autophagy genes, Atg5, Atg14, or Atg16L1 results in tumour rejection. Despite a significant reduction in the total number of CD8+ tumour infiltrating lymphocytes (TILs), loss of Atg5 causes a profound shift toward IFNg and TNF producing effector memory cells. Consistent with this, adoptive transfer with Atg5-/- T cells promotes tumour control. Mechanistically, CD8+ T cells lacking autophagy exhibit enhanced glucose metabolism resulting in global changes in histone trimethylation and increased transcriptional activation of effector target genes. Restricting glucose is sufficient to suppress autophagy-dependent increases in effector function and reverse alterations in histone trimethylation. These findings identify autophagy as a cell-autonomous negative regulator of CD8+ T cell anti-tumour immunity with implications on T cell-based immunotherapy.

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IRF4 modulates CD8 T cell sensitivity to IL-2 family cytokines

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Project description:Host immune response is a fundamental mechanism for attenuating cancer progression. Here we report a pivotal role of the DNA demethylase and tumor suppressor TET2 played in host antitumor immunity. Deletion of Tet2 dramatically elevated the IL-6 level in Tet2-/- mice upon tumor challenge. The elevated IL-6 greatly stimulated the immunosuppressive granulocytic myeloid-derived suppressor cells (G-MDSCs), which in turn significantly reduced CD8+ T cells upon tumor challenge. Consequently, systematic knockout of the Tet2 in mice led to accelerated syngeneic tumor growth, which was constrained by anti-PD-1 blockade. Removal of G-MDSCs by the anti-mouse Ly6g Ab restored the numbers of CD8+ T cells in Tet2-/- mice and rebooted their anti-tumor activity. Importantly, anti-IL-6 Ab treatment blocked the expansion of G-MDSCs and inhibited syngeneic tumor growth. Collectively, these findings reveal a TET2-mediated IL-6/G-MDSC/CD8+ T immune response cascade that safeguards host adaptive anti-tumor immunity, offering a cell non-autonomous mechanism of TET2 for tumor suppression.

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Project description:Cellular senescence is a stress response known to activate innate immunity. However, how senescent cells interact with the adaptive immune system remains largely unexplored. Here, we show that senescent cells display an enhanced MHC class I antigen processing and presentation. Furthermore, senescent cells present an altered immunopeptidome including unique non-mutated antigens that can be recognized by specific CD8 T cells. Immunization of mice with senescent cancer cells triggers strong protective CD8-dependent antitumor responses, superior to immunogenic cell death. Similarly, induction of senescence in human primary cancer cells hyperactivates their cognate reactive CD8 T cell. Our study indicates that immunization with senescent cells provides a sustained source of antigens that strongly activate anti-tumor CD8 T cells.

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