Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

PEACE Consortium, TRACERx Renal Consortium, Lewis Au, Emine Hatipoglu, Marc Robert de Massy, Kevin Litchfield, Gordon Beattie, Andrew Rowan, Desiree Schnidrig, Rachael Thompson, Fiona Byrne, Stuart Horswell, Nicos Fotiadis, Steve Hazell, David Nicol, Scott T.C. Shepherd, Annika Fendler, Robert Mason, Lyra Del Rosario, Kim EdmondsKarla Lingard, Sarah Sarker, Mary Mangwende, Eleanor Carlyle, Jan Attig, Kroopa Joshi, Imran Uddin, Pablo D. Becker, Mariana Werner Sunderland, Ayse Akarca, Ignazio Puccio, William W. Yang, Tom Lund, Kim Dhillon, Marcos Duran Vasquez, Peter Parker, David Moore, Crispin Hiley, Debra Josephs, Ashish Chandra, James Spicer, Sarah Rudman, Andrew Tutt, Ian Tomlinson, Ben Challacombe, Simon Chowdhury, Karen Harrison-Phipps, Peter Hill, Catherine Horsfield, Tim O'Brien, Jonathon Olsburgh, Alexander Polson

Research output: Contribution to journalArticlepeer-review

110 Citations (Scopus)

Abstract

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Original languageEnglish
Pages (from-to)1497-1518.e11
JournalCANCER CELL
Volume39
Issue number11
DOIs
Publication statusPublished - 8 Nov 2021

Keywords

  • anti-PD-1
  • autopsy
  • clear cell renal cell carcinoma
  • human endogenous retrovirus
  • multiregion
  • nivolumab
  • T cell receptor
  • TCR clonal maintenance
  • TCR clonal replacement

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