![]() This highlights the challenges confronting characterization of the cells responsible for the activity of T cell-targeting immunotherapies.įor this study, we used peripheral blood and tissue biospecimens obtained from the first-in-human clinical trial of neoadjuvant anti-PD-1 (nivolumab) in resectable non-small cell lung cancer 8 (NSCLC identifier: NCT02259621 Fig. Indeed, MANA-specific T cells represent a small fraction of total TIL 2, 7, particularly in lung cancer, in which they have been shown to selectively upregulate CD39. ![]() A related problem is the paucity of information regarding the differences between MANA-specific TIL in ICB-responsive versus resistant tumours. ![]() However, a fundamental limitation in the current understanding of the T cell functional programs that underpin the response to ICB has been the absence of transcriptional profiling of true MANA-specific TIL. Improving response rates to ICB will require an understanding of the functional state of tumour-specific T cells, particularly in the tumour microenvironment. The association of improved anti-PD-1 and anti-PD-L1 clinical responses with high tumour mutational burden 5 strongly suggests that MANA are important targets of anti-tumour immunity induced by PD-1 blockade.ĭespite the success of immune checkpoint blockade (ICB) in improving clinical outcomes, most cancers still do not respond 6. Early studies focused on tumour-associated antigens, whereas recent work has shifted attention to T cell recognition of mutation-associated neoantigens (MANA), owing to the large numbers of somatic mutations acquired by many cancers during their development 4. The efficacy of PD-1- and PD-L1-blocking agents is predicated upon CD8 T cell-mediated anti-tumour immunity 1. These findings provide important insights for overcoming resistance to PD-1 blockade. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIT high TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. ![]() Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay 3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). However, the majority of TIL do not recognize tumour antigens 2, and little is known about transcriptional programs of MANA-specific TIL. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). PD-1 blockade unleashes CD8 T cells 1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Nature volume 596, pages 126–132 ( 2021) Cite this article Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers ![]()
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