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Nat Genet DOI:10.1038/s41588-018-0200-2

Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors.

Publication TypeJournal Article
Year of Publication2018
AuthorsMiao, D, Margolis, CA, Vokes, NI, Liu, D, Taylor-Weiner, A, Wankowicz, SM, Adeegbe, D, Keliher, D, Schilling, B, Tracy, A, Manos, M, Chau, NG, Hanna, GJ, Polak, P, Rodig, SJ, Signoretti, S, Sholl, LM, Engelman, JA, Getz, G, Jänne, PA, Haddad, RI, Choueiri, TK, Barbie, DA, Haq, R, Awad, MM, Schadendorf, D, F Hodi, S, Bellmunt, J, Wong, K-K, Hammerman, P, Van Allen, EM
JournalNat Genet
Date Published2018 09
KeywordsCohort Studies, Exome, Genomics, Humans, Immunity, Microsatellite Repeats, Mutation, Neoplasms

Tumor mutational burden correlates with response to immune checkpoint blockade in multiple solid tumors, although in microsatellite-stable tumors this association is of uncertain clinical utility. Here we uniformly analyzed whole-exome sequencing (WES) of 249 tumors and matched normal tissue from patients with clinically annotated outcomes to immune checkpoint therapy, including radiographic response, across multiple cancer types to examine additional tumor genomic features that contribute to selective response. Our analyses identified genomic correlates of response beyond mutational burden, including somatic events in individual driver genes, certain global mutational signatures, and specific HLA-restricted neoantigens. However, these features were often interrelated, highlighting the complexity of identifying genetic driver events that generate an immunoresponsive tumor environment. This study lays a path forward in analyzing large clinical cohorts in an integrated and multifaceted manner to enhance the ability to discover clinically meaningful predictive features of response to immune checkpoint blockade.


Alternate JournalNat Genet
PubMed ID30150660
PubMed Central IDPMC6119118
Grant ListK08 CA188615 / CA / NCI NIH HHS / United States
T32 HG002295 / HG / NHGRI NIH HHS / United States
T32 CA009172 / CA / NCI NIH HHS / United States
R01 CA140594 / CA / NCI NIH HHS / United States
R01 CA166480 / CA / NCI NIH HHS / United States
R01 CA227388 / CA / NCI NIH HHS / United States