Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers Academic Article uri icon

  •  
  • Overview
  •  
  • Research
  •  
  • Identity
  •  
  • Additional Document Info
  •  
  • View All
  •  

abstract

  • AbstractPD-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.

authors

  • Caushi, Justina X
  • Zhang, Jiajia
  • Ji, Zhicheng
  • Vaghasia, Ajay
  • Zhang, Boyang
  • Hsiue, Emily Han-Chung
  • Mog, Brian J
  • Hou, Wenpin
  • Justesen, Sune
  • Blosser, Richard
  • Tam, Ada
  • Anagnostou, Valsamo
  • Cottrell, Tricia R
  • Guo, Haidan
  • Chan, Hok Yee
  • Singh, Dipika
  • Thapa, Sampriti
  • Dykema, Arbor G
  • Burman, Poromendro
  • Choudhury, Begum
  • Aparicio, Luis
  • Cheung, Laurene S
  • Lanis, Mara
  • Belcaid, Zineb
  • El Asmar, Margueritta
  • Illei, Peter B
  • Wang, Rulin
  • Meyers, Jennifer
  • Schuebel, Kornel
  • Gupta, Anuj
  • Skaist, Alyza
  • Wheelan, Sarah
  • Naidoo, Jarushka
  • Marrone, Kristen A
  • Brock, Malcolm
  • Ha, Jinny
  • Bush, Errol L
  • Park, Bernard J
  • Bott, Matthew
  • Jones, David R
  • Reuss, Joshua E
  • Velculescu, Victor E
  • Chaft, Jamie E
  • Kinzler, Kenneth W
  • Zhou, Shibin
  • Vogelstein, Bert
  • Taube, Janis M
  • Hellmann, Matthew D
  • Brahmer, Julie R
  • Merghoub, Taha
  • Forde, Patrick M
  • Yegnasubramanian, Srinivasan
  • Ji, Hongkai
  • Pardoll, Drew M
  • Smith, Kellie N

publication date

  • August 5, 2021

has subject area