Project description:Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but most patients do not respond. PD-1 blockade “unleashes” CD8 T cells, including those specific for mutation-associated neoantigens (MANA), but factors in the tumor microenvironment can inhibit responses by dampening MANA-specific T cell function. Recent advances in single cell transcriptomics are revealing global T cell dysfunction programs in tumor-infiltrating lymphocytes (TIL). However, the vast majority of TIL do not recognize tumor antigens and little is known about transcriptional programs of true MANA-specific TIL. Here, we use an integrated approach to identify MANA-specific T cell clones using the MANA functional expansion of specific T cells (MANAFEST) assay in neoadjuvant anti-PD-1-treated lung cancers and use their TCR CDR3 as barcodes to track them and analyze their transcriptional programs and function in the tumor microenvironment using single cell RNA sequencing. We find both MANA-and virus-specific clones in TIL and adjacent normal lung, regardless of response status. MANA-specific, influenza (flu)-specific and EBV-specific TIL each have unique transcriptional programs. Most MANA-specific clones are tissue resident memory (TRM) cells, an incompletely activated cytolytic program, including EOMES deficiency, and higher levels of genes encoding T cell inhibitory molecules and Tox2. Notably, MANA-specific T cells express low levels of IL-7R and are functionally less responsive to IL-7 compared with tissue-resident flu-specific clones. MANA-specific clones from anti-PD-1 non-responding tumors express TCR with markedly lower ligand-dependent signaling capability, are largely confined to HOBIThi TRM subsets and coordinately up-regulate genes encoding specific checkpoints, killer inhibitory receptors, and intracellular inhibitors of T cell activation and cytotoxicity. These findings provide mechanistic and potential therapeutic insights into overcoming resistance to PD-1 blockade.

			Action	DRS
	SRR5629710.fastq.gz	Fastqsanger.gz
	SRR5629710_1.fastq.gz	Fastqsanger.gz
	SRR5629710_2.fastq.gz	Fastqsanger.gz
	SRR5629711.fastq.gz	Fastqsanger.gz
	SRR5629711_1.fastq.gz	Fastqsanger.gz

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De novo epigenetic programs inhibit PD-1 blockade-mediated T-cell rejuvenation

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