Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.
View/ Open
Date
2021-11-08Author
Au, L
Hatipoglu, E
Robert de Massy, M
Litchfield, K
Beattie, G
Rowan, A
Schnidrig, D
Thompson, R
Byrne, F
Horswell, S
Fotiadis, N
Hazell, S
Nicol, D
Shepherd, STC
Fendler, A
Mason, R
Del Rosario, L
Edmonds, K
Lingard, K
Sarker, S
Mangwende, M
Carlyle, E
Attig, J
Joshi, K
Uddin, I
Becker, PD
Sunderland, MW
Akarca, A
Puccio, I
Yang, WW
Lund, T
Dhillon, K
Vasquez, MD
Ghorani, E
Xu, H
Spencer, C
López, JI
Green, A
Mahadeva, U
Borg, E
Mitchison, M
Moore, DA
Proctor, I
Falzon, M
Pickering, L
Furness, AJS
Reading, JL
Salgado, R
Marafioti, T
Jamal-Hanjani, M
PEACE Consortium,
Kassiotis, G
Chain, B
Larkin, J
Swanton, C
Quezada, SA
Turajlic, S
TRACERx Renal Consortium,
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
PEACE Consortium
TRACERx Renal Consortium
CD8-Positive T-Lymphocytes
Humans
Endogenous Retroviruses
Carcinoma, Renal Cell
Kidney Neoplasms
Receptors, Antigen, T-Cell
Prospective Studies
Gene Expression Profiling
Sequence Analysis, RNA
Genomics
Tumor Escape
Drug Resistance, Neoplasm
Clinical Trials, Phase II as Topic
Single-Cell Analysis
Tumor Microenvironment
Whole Exome Sequencing
Nivolumab
Immune Checkpoint Inhibitors
Language
eng
Date accepted
2021-10-06
Citation
Cancer cell, 2021, 39 (11), pp. 1497 - 1518.e11
Publisher
CELL PRESS