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

Justina X. Caushi, Jiajia Zhang, Zhicheng Ji, Ajay Vaghasia, Boyang Zhang, Emily Han-Chung Hsiue, Brian J. Mog, Wenpin Hou, Sune Justesen, Richard Blosser, Ada Tam, Valsamo Anagnostou, Tricia R. Cottrell, Haidan Guo, Hok Yee Chan, Dipika Singh, Sampriti Thapa, Arbor G. Dykema, Poromendro Burman, Begum Choudhury, Luis Aparicio, Laurene S. Cheung, Mara Lanis, Zineb Belcaid, Margueritta El Asmar, Peter B. Illei, Rulin Wang, Jennifer Meyers, Kornel Schuebel, Anuj Gupta, Alyza Skaist, Sarah Wheelan, Jarushka Naidoo, Kristen A. Marrone, Malcolm Brock, Jinny Ha, Errol L. Bush, Bernard J. Park, Matthew Bott, David R. Jones, Joshua E. Reuss, Victor E. Velculescu, Jamie E. Chaft, Kenneth W. Kinzler, Shibin Zhou, Bert Vogelstein, Janis M. Taube, Matthew D. Hellmann, Julie R. Brahmer, Taha Merghoub, Patrick M. Forde, Srinivasan Yegnasubramanian (), Hongkai Ji (), Drew M. Pardoll () and Kellie N. Smith ()
Additional contact information
Justina X. Caushi: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Jiajia Zhang: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Zhicheng Ji: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University
Ajay Vaghasia: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Boyang Zhang: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University
Emily Han-Chung Hsiue: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Brian J. Mog: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Wenpin Hou: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University
Sune Justesen: Immunitrack
Richard Blosser: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Ada Tam: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Valsamo Anagnostou: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Tricia R. Cottrell: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Haidan Guo: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Hok Yee Chan: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Dipika Singh: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Sampriti Thapa: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Arbor G. Dykema: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Poromendro Burman: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Begum Choudhury: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Luis Aparicio: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Laurene S. Cheung: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Mara Lanis: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Zineb Belcaid: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Margueritta El Asmar: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Peter B. Illei: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Rulin Wang: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Jennifer Meyers: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Kornel Schuebel: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Anuj Gupta: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Alyza Skaist: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sarah Wheelan: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Jarushka Naidoo: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Kristen A. Marrone: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Malcolm Brock: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Jinny Ha: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Errol L. Bush: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bernard J. Park: Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine
Matthew Bott: Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine
David R. Jones: Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine
Joshua E. Reuss: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Victor E. Velculescu: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Jamie E. Chaft: Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine
Kenneth W. Kinzler: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Shibin Zhou: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bert Vogelstein: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Janis M. Taube: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Matthew D. Hellmann: Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine
Julie R. Brahmer: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Taha Merghoub: Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine
Patrick M. Forde: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Srinivasan Yegnasubramanian: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Hongkai Ji: Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University
Drew M. Pardoll: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
Kellie N. Smith: Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins

Nature, 2021, vol. 596, issue 7870, 126-132

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03752-4

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