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 ChoudhuryLuis 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, Kellie N. Smith

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)126-132
Number of pages7
Issue number7870
StatePublished - Aug 5 2021

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers'. Together they form a unique fingerprint.

Cite this