Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers Journal Article
| Authors: | Caushi, J. X.; Zhang, J.; Ji, Z.; Vaghasia, A.; Zhang, B.; Hsiue, E. H. C.; Mog, B. J.; Hou, W.; Justesen, S.; Blosser, R.; Tam, A.; Anagnostou, V.; Cottrell, T. R.; Guo, H.; Chan, H. Y.; Singh, D.; Thapa, S.; Dykema, A. G.; Burman, P.; Choudhury, B.; Aparicio, L.; Cheung, L. S.; Lanis, M.; Belcaid, Z.; El Asmar, M.; Illei, P. B.; Wang, R.; Meyers, J.; Schuebel, K.; Gupta, A.; Skaist, A.; Wheelan, S.; Naidoo, J.; Marrone, K. A.; Brock, M.; Ha, J.; Bush, E. L.; Park, B. J.; Bott, M.; Jones, D. R.; Reuss, J. E.; Velculescu, V. E.; Chaft, J. E.; Kinzler, K. W.; Zhou, S.; Vogelstein, B.; Taube, J. M.; Hellmann, M. D.; Brahmer, J. R.; Merghoub, T.; Forde, P. M.; Yegnasubramanian, S.; Ji, H.; Pardoll, D. M.; Smith, K. N. |
| Article Title: | Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers |
| Abstract: | PD-1 blockade unleashes CD8 T cells1, 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 antigens2, 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 assay3 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. © 2021, The Author(s). |
| Keywords: | signal transduction; controlled study; cd8+ t lymphocyte; tumor associated leukocyte; cell function; gene expression; t lymphocyte receptor; cell migration; upregulation; cell activation; cell expansion; cell homing; nuclear reprogramming; non small cell lung cancer; tumor microenvironment; interleukin 7 receptor; nivolumab; human; article; rna sequencing |
| Journal Title: | Nature |
| Volume: | 596 |
| Issue: | 7870 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2021-08-05 |
| Start Page: | 126 |
| End Page: | 132 |
| Language: | English |
| DOI: | 10.1038/s41586-021-03752-4 |
| PUBMED: | 34290408 |
| PROVIDER: | scopus |
| PMCID: | PMC8338555 |
| DOI/URL: | |
| Notes: | Article -- Erratum Published, DOI: 10.1038/s41586-021-03893-6 -- Figure labeling errors -- Source: Scopus |
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