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

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...

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Published in:	Nature (London) Vol. 596; no. 7870; pp. 126 - 132
Main Authors:	Caushi, Justina X., Zhang, Jiajia, Ji, Zhicheng, Vaghasia, Ajay, Zhang, Boyang, Hsiue, Emily Han-Chung, Mog, Brian J., Hou, Wenpin, Justesen, Sune, Blosser, Richard, Tam, Ada, Anagnostou, Valsamo, Cottrell, Tricia R., Guo, Haidan, Chan, Hok Yee, Singh, Dipika, Thapa, Sampriti, Dykema, Arbor G., Burman, Poromendro, Choudhury, Begum, Aparicio, Luis, Cheung, Laurene S., Lanis, Mara, Belcaid, Zineb, El Asmar, Margueritta, Illei, Peter B., Wang, Rulin, Meyers, Jennifer, Schuebel, Kornel, Gupta, Anuj, Skaist, Alyza, Wheelan, Sarah, Naidoo, Jarushka, Marrone, Kristen A., Brock, Malcolm, Ha, Jinny, Bush, Errol L., Park, Bernard J., Bott, Matthew, Jones, David R., Reuss, Joshua E., Velculescu, Victor E., Chaft, Jamie E., Kinzler, Kenneth W., Zhou, Shibin, Vogelstein, Bert, Taube, Janis M., Hellmann, Matthew D., Brahmer, Julie R., Merghoub, Taha, Forde, Patrick M., Yegnasubramanian, Srinivasan, Ji, Hongkai, Pardoll, Drew M., Smith, Kellie N.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 05.08.2021
Subjects:	13 13/106 13/109 13/31 42 45 45/23 45/91 631/250/1619/554/1775 631/250/1619/554/1834 631/250/2152/1566 631/250/251 631/250/580 Antigens, Neoplasm - genetics Antigens, Neoplasm - immunology Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - immunology CD8-Positive T-Lymphocytes - immunology Cells, Cultured Gene Expression Regulation Humanities and Social Sciences Humans Immune Checkpoint Inhibitors - therapeutic use Immunologic Memory Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - immunology Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - metabolism multidisciplinary Programmed Cell Death 1 Receptor - antagonists & inhibitors Receptors, Interleukin-7 - immunology RNA-Seq Science Science (multidisciplinary) Single-Cell Analysis Transcriptome - genetics Tumor Microenvironment
ISSN:	0028-0836, 1476-4687, 1476-4687
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Summary:	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. Single-cell RNA sequencing and T cell receptor sequencing are combined to identify transcriptional programs specific to mutation-associated neoantigen-specific T cells in non-small cell lung cancers treated with anti-PD-1, providing insights into resistance to PD-1 blockade.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-021-03752-4