Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers.

> 商业许可源文 · EUROPE_PMC · [CC-BY](https://creativecommons.org/licenses/by/)

书目信息

引用：Caushi JX, Zhang J, Ji Z, Vaghasia A, Zhang B, Hsiue EH, Mog BJ, Hou W, Justesen S, Blosser R, Tam A, Anagnostou V, Cottrell TR, Guo H, Chan HY, Singh D, Thapa S, Dykema AG, Burman P, Choudhury B, Aparicio L, Cheung LS, Lanis M, Belcaid Z, El Asmar M, Illei PB, Wang R, Meyers J, Schuebel K, Gupta A, Skaist A, Wheelan S, Naidoo J, Marrone KA, Brock M, Ha J, Bush EL, Park BJ, Bott M, Jones DR, Reuss JE, Velculescu VE, Chaft JE, Kinzler KW, Zhou S, Vogelstein B, Taube JM, Hellmann MD, Brahmer JR, Merghoub T, Forde PM, Yegnasubramanian S, Ji H, Pardoll DM, Smith KN. (2021). Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature. PMID 34290408 · PMC8338555 · DOI 10.1038/s41586-021-03752-4

证据类型：PRIMARY_RESEARCH

主题：single-cell

被引次数（采集时）：480

原始记录：[Europe PMC](https://europepmc.org/article/MED/34290408)

来源许可：[CC-BY](https://creativecommons.org/licenses/by/)

作者摘要（按来源许可复用）

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. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens 2 , and little is known about transcriptional programs of MANA-specific TIL. 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). 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. 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. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. 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. 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. These findings provide important insights for overcoming resistance to PD-1 blockade.

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