Journal
SCIENCE
Volume 348, Issue 6230, Pages 124-128Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaa1348
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Funding
- Geoffrey Beene Cancer Research Center
- Society for Memorial Sloan Kettering Cancer Center
- Lung Cancer Research Foundation
- Frederick Adler Chair Fund
- One Ball Matt Memorial Golf Tournament
- Queen Wilhelmina Cancer Research Award
- STARR Foundation
- Ludwig Trust
- Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Cancer Research Grant
- Versus Arthritis
- Cancer Research UK [21141] Funding Source: researchfish
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Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy.
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