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LAG3 and PD1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN gamma-dependent anti-tumor immunity

ABSTRACT: LAG3 and PD1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN gamma-dependent anti-tumor immunity

PROVIDER: PRJNA1093086 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28493376_1.fastq.gz	Fastqsanger.gz
	SRR28493376_2.fastq.gz	Fastqsanger.gz
	SRR28493377_1.fastq.gz	Fastqsanger.gz
	SRR28493377_2.fastq.gz	Fastqsanger.gz
	SRR28493378_1.fastq.gz	Fastqsanger.gz

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LAG3 and PD1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN gamma-dependent anti-tumor immunity

Project description:Combined nivolumab (anti-PD1) and relatlimab (anti-LAG3) have shown enhanced effectiveness in melanoma patients. However, how these two receptors work together to hinder anti-tumor immunity remains unclear. Our study demonstrates that PD1/LAG3-deficient CD8+ T cells with more effectively clearing tumors and survive longer in melanoma mouse models. These PD1/LAG3-deficient CD8+ T cells have unique transcriptional profiles, broad TCR clonality, and enriched effector-like and interferon-responsive genes, leading to increased IFN gamma release indicating functionality. PD1 and LAG3 together drive T cell exhaustion, with a significant impact on TOX modulation. Mechanistically, autocrine IFN gamma signaling is crucial for enhancing anti-tumor immunity in PD1/LAG3-deficient CD8+ T cells, providing insights into the enhanced efficacy of combined PD1 and LAG3 targeting.

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