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

Miao D1,2, Margolis CA1,2, Vokes NI1,2, Liu D1,2, Taylor-Weiner A1,2, Wankowicz SM1,2, Adeegbe D3, Keliher D1,2, Schilling B4, Tracy A2, Manos M1, Chau NG1, Hanna GJ1, Polak P2, Rodig SJ1,5, Signoretti S1,5, Sholl LM1,5, Engelman JA6, Getz G2,6,7,8, Jänne PA1, Haddad RI1, Choueiri TK1, Barbie DA1, Haq R1,2, Awad MM1, Schadendorf D1,9, Hodi FS1, Bellmunt J1, Wong KK1,3, Hammerman P1, Van Allen EM10,11.

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Abstract

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.