TY - JOUR
T1 - Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers
AU - Caushi, Justina X.
AU - Zhang, Jiajia
AU - Ji, Zhicheng
AU - Vaghasia, Ajay
AU - Zhang, Boyang
AU - Hsiue, Emily Han Chung
AU - Mog, Brian J.
AU - Hou, Wenpin
AU - Justesen, Sune
AU - Blosser, Richard
AU - Tam, Ada
AU - Anagnostou, Valsamo
AU - Cottrell, Tricia R.
AU - Guo, Haidan
AU - Chan, Hok Yee
AU - Singh, Dipika
AU - Thapa, Sampriti
AU - Dykema, Arbor G.
AU - Burman, Poromendro
AU - Choudhury, Begum
AU - Aparicio, Luis
AU - Cheung, Laurene S.
AU - Lanis, Mara
AU - Belcaid, Zineb
AU - El Asmar, Margueritta
AU - Illei, Peter B.
AU - Wang, Rulin
AU - Meyers, Jennifer
AU - Schuebel, Kornel
AU - Gupta, Anuj
AU - Skaist, Alyza
AU - Wheelan, Sarah
AU - Naidoo, Jarushka
AU - Marrone, Kristen A.
AU - Brock, Malcolm
AU - Ha, Jinny
AU - Bush, Errol L.
AU - Park, Bernard J.
AU - Bott, Matthew
AU - Jones, David R.
AU - Reuss, Joshua
AU - Velculescu, Victor E.
AU - Chaft, Jamie E.
AU - Kinzler, Kenneth W.
AU - Zhou, Shibin
AU - Vogelstein, Bert
AU - Taube, Janis M.
AU - Hellmann, Matthew D.
AU - Brahmer, Julie R.
AU - Merghoub, Taha
AU - Forde, Patrick M.
AU - Yegnasubramanian, Srinivasan
AU - Ji, Hongkai
AU - Pardoll, Drew M.
AU - Smith, Kellie N.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/8/5
Y1 - 2021/8/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85110991277&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110991277&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03752-4
DO - 10.1038/s41586-021-03752-4
M3 - Article
C2 - 34290408
AN - SCOPUS:85110991277
SN - 0028-0836
VL - 596
SP - 126
EP - 132
JO - Nature
JF - Nature
IS - 7870
ER -