Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.
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IF: 38.585
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Cited by: 85
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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.

Keywords

mIF
Omics
Seurat
Spatial Transcriptomics
Gene Expression
T cell receptor
TCR clonal maintenance
TCR clonal replacement
anti-PD-1
autopsy
clear cell renal cell carcinoma
human endogenous retrovirus
multiregion
nivolumab

Authors

Au, Lewis
Hatipoglu, Emine
Robert de Massy, Marc
Litchfield, Kevin
Beattie, Gordon
Rowan, Andrew
Schnidrig, Desiree
Thompson, Rachael
Byrne, Fiona
Horswell, Stuart
Fotiadis, Nicos
Hazell, Steve
Nicol, David
Shepherd, Scott T C
Fendler, Annika
Mason, Robert
Del Rosario, Lyra
Edmonds, Kim
Lingard, Karla
Sarker, Sarah
Mangwende, Mary
Carlyle, Eleanor
Attig, Jan
Joshi, Kroopa
Uddin, Imran
Becker, Pablo D
Sunderland, Mariana Werner
Akarca, Ayse
Puccio, Ignazio
Yang, William W
Lund, Tom
Dhillon, Kim
Vasquez, Marcos Duran
Ghorani, Ehsan
Xu, Hang
Spencer, Charlotte
López, José I
Green, Anna
Mahadeva, Ula
Borg, Elaine
Mitchison, Miriam
Moore, David A
Proctor, Ian
Falzon, Mary
Pickering, Lisa
Furness, Andrew J S
Reading, James L
Salgado, Roberto
Marafioti, Teresa
Jamal-Hanjani, Mariam
Kassiotis, George
Chain, Benny
Larkin, James
Swanton, Charles
Quezada, Sergio A
Turajlic, Samra

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