期刊
CELL
卷 171, 期 4, 页码 934-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2017.09.028
关键词
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资金
- Bristol-Myers Squibb
- Pershing Square Sohn Cancer Research Foundation
- PaineWebber Chair
- Stand Up 2 Cancer
- Memorial Sloan Kettering Cancer Center [5P30 CA008748-50]
- STARR Cancer Consortium
- Abraxis
- Amgen
- Bionomics
- EMD Serono
- Immune Design
- Immunogen
- Merck
- NantKwest
- OncoSec
- Genentech
- Incyte
- Ono
- Seattle Genetics
- AbbVie
- Aduro
- Bayer
- Jounce Therapeutics
- stock shareholder of Jounce Therapeutics
- Novartis
- GlaxoSmithKline
- MedImmune
- Castle Biosciences
- Polynoma
- Green Peptide
- eTheRNA
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumabnaive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.
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