| Literature DB >> 29033130 |
Nadeem Riaz1, Jonathan J Havel2, Vladimir Makarov3, Alexis Desrichard2, Walter J Urba4, Jennifer S Sims3, F Stephen Hodi5, Salvador Martín-Algarra6, Rajarsi Mandal7, William H Sharfman8, Shailender Bhatia9, Wen-Jen Hwu10, Thomas F Gajewski11, Craig L Slingluff12, Diego Chowell3, Sviatoslav M Kendall3, Han Chang13, Rachna Shah2, Fengshen Kuo14, Luc G T Morris15, John-William Sidhom16, Jonathan P Schneck16, Christine E Horak13, Nils Weinhold17, Timothy A Chan18.
Abstract
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 ipilimumab-naive, 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.Entities:
Keywords: T cell receptor repertoire; clonal evolution/clonal selection; immunotherapy; ipilimumab; melanoma; neoantigen load; nivolumab; tumor immune evasion; tumor microenvironment; tumor mutation load/tumor mutation burden
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Year: 2017 PMID： 29033130 PMCID： PMC5685550 DOI： 10.1016/j.cell.2017.09.028
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582