期刊
CANCER CELL
卷 39, 期 11, 页码 1497-+出版社
CELL PRESS
DOI: 10.1016/j.ccell.2021.10.001
关键词
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资金
- Royal Marsden NHS Foundation Trust
- National Institute for Health Research (NIHR) Biomedical Research Center (BRC) at the Royal Marsden Hospital
- Institute of Cancer Research (ICR) [A80]
- Cancer Research UK (CRUK) [17767]
- NIHR BRC at the Royal Marsden Hospital
- Institute of Cancer Research [A109]
- Francis Crick Institute - UK Medical Research Council (CRUK) [FC001169, FC001988, FC001099]
- Wellcome Trust [FC001169, FC001988, FC001099]
- CRUK City of London Centre Award [C7893/A26233]
- CRUK UCL Award [C416/A26233]
- Cancer Immunotherapy Accelerator Award (CITA-CRUK) [C33499/A20265]
- National Institute for Health Research UCL Hospitals Biomedical Research Centre
- Experimental Histopathology Team
- Bristol-Myers Squibb
- UK Medical Research Council [FC001169, FC001988, FC001099]
The ADAPTeR study aimed to investigate the mechanism of therapeutic response to nivolumab in metastatic clear cell renal cell carcinoma, with genomic analysis showing no correlation between tumor molecular features and response. Pre-existing immunity may play a key role in predicting clinical response.
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.
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