Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers.
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.
Caushi, JX; Zhang, J; Ji, Z; Vaghasia, A; Zhang, B; Hsiue, EH-C; 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
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