Tumor and microenvironment evolution during immunotherapy with nivolumab Journal Article
| Authors: | Riaz, N.; Havel, J. J.; Makarov, V.; Desrichard, A.; Urba, W. J.; Sims, J. S.; Hodi, F. S.; Martín-Algarra, S.; Mandal, R.; Sharfman, W. H.; Bhatia, S.; Hwu, W. J.; Gajewski, T. F.; Slingluff, C. L. Jr; Chowell, D.; Kendall, S. M.; Chang, H.; Shah, R.; Kuo, F.; Morris, L. G. T.; Sidhom, J. W.; Schneck, J. P.; Horak, C. E.; Weinhold, N.; Chan, T. A. |
| Article Title: | Tumor and microenvironment evolution during immunotherapy with nivolumab |
| 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. Mutation burden decreases with successful checkpoint blockade therapy in patients with melanoma, suggesting that selection against mutant neoepitopes may be a critical mechanism of action of Nivolumab. © 2017 Elsevier Inc. |
| Keywords: | human tissue; treatment response; gene mutation; human cell; major clinical study; t lymphocyte; ipilimumab; cancer immunotherapy; melanoma; transcription initiation; t lymphocyte receptor; antigen; immunotherapy; upregulation; transcriptome; cell expansion; immunocompetent cell; genetic heterogeneity; tumor microenvironment; clonal evolution; nivolumab; human; priority journal; article; tumor immune evasion; whole exome sequencing; clonal evolution/clonal selection; neoantigen load; t cell receptor repertoire; tumor mutation load/tumor mutation burden |
| Journal Title: | Cell |
| Volume: | 171 |
| Issue: | 4 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2017-11-02 |
| Start Page: | 934 |
| End Page: | 949.e15 |
| Language: | English |
| DOI: | 10.1016/j.cell.2017.09.028 |
| PROVIDER: | scopus |
| PMCID: | PMC5685550 |
| PUBMED: | 29033130 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2017 -- Source: Scopus |
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