Journal
NATURE
Volume 596, Issue 7870, Pages 126-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03752-4
Keywords
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Funding
- Lung Cancer Foundation of America
- Mark Foundation for Cancer Research
- SU2C/Mark Foundation Lung Cancer Dream Team Convergence Award
- SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team
- Bristol-Myers Squibb
- SU2C DCS International Translational Cancer Research Dream Team [SU2C-AACR-DT1415]
- IASLC Foundation
- Swim Across America
- LUNGevity Foundation
- Commonwealth Foundation
- Banks Family Foundation
- PMAC from Juntendo University
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, The Virginia
- D.K. Ludwig Fund for Cancer Research
- Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering
- Cancer Research Institute
- Parker Institute for Cancer Immunotherapy
- Lustgarten Foundation for Pancreatic Cancer Research
- Conquer Cancer Foundation of ASCO
- Bloomberg Philanthropies
- Maryland Cigarette Restitution Fund
- V Foundation
- Allegheny Health Network-Johns Hopkins Research Fund
- Damon Runyon Cancer Research Foundation [CI-98-18]
- US NIH [R37CA251447, R01HG010889, R01HG009518, R01CA121113, R01CA217169, R01CA240472, CA62924, T32 CA193145, T32 CA009110, T32 GM136577]
- NIH Cancer Center Support Grants [P30 CA008748, P30 CA006973]
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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.
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 HOBIThigh 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.
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