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.
journal_name
Celljournal_title
Cellauthors
Riaz N,Havel JJ,Makarov V,Desrichard A,Urba WJ,Sims JS,Hodi FS,Martín-Algarra S,Mandal R,Sharfman WH,Bhatia S,Hwu WJ,Gajewski TF,Slingluff CL Jr,Chowell D,Kendall SM,Chang H,Shah R,Kuo F,Morris LGT,Sidhom JW,Schdoi
10.1016/j.cell.2017.09.028subject
Has Abstractpub_date
2017-11-02 00:00:00pages
934-949.e16issue
4eissn
0092-8674issn
1097-4172pii
S0092-8674(17)31122-4journal_volume
171pub_type
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