Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.
Cell
; 171(4): 934-949.e16, 2017 Nov 02.
Article
em En
| MEDLINE
| ID: mdl-29033130
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.
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Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Microambiente Tumoral
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Imunoterapia
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Melanoma
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Anticorpos Monoclonais
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2017
Tipo de documento:
Article