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

Au, Lewis, Hatipoglu, Emine, Robert de Massy, Marc, Litchfield, Kevin, Beattie, Gordon, Rowan, Andrew, Schnidrig, Desiree, Thompson, Rachael, Byrne, Fiona, Horswell, Stuart
et al (show 195 more authors) (2021) Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma. Cancer Cell, 39 (11). 1497-1518.e11.

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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<sup>+</sup> 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.

Item Type: Article
Uncontrolled Keywords: 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, Nivolumab, Immune Checkpoint Inhibitors, Exome Sequencing
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 20 Dec 2021 08:10
Last Modified: 04 Feb 2023 02:18
DOI: 10.1016/j.ccell.2021.10.001
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