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Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition

Authors
  • Chat, Vylyny1, 2, 3
  • Ferguson, Robert1, 2, 3
  • Simpson, Danny1, 2, 3
  • Kazlow, Esther1, 2, 3
  • Lax, Rebecca1, 2, 3
  • Moran, Una1, 3, 4, 5
  • Pavlick, Anna3, 4
  • Frederick, Dennie6
  • Boland, Genevieve6
  • Sullivan, Ryan6
  • Ribas, Antoni7
  • Flaherty, Keith6
  • Osman, Iman1, 3, 4, 5
  • Weber, Jeffrey1, 3, 4
  • Kirchhoff, Tomas1, 2, 3
  • 1 New York University School of Medicine, Laura and Issac Perlmutter Cancer Center, 522 First Avenue, New York, NY, 10016, USA , New York (United States)
  • 2 New York University School of Medicine, Departments of Population Health and Environmental Medicine, New York, NY, USA , New York (United States)
  • 3 New York University School of Medicine, The Interdisciplinary Melanoma Cooperative Group, New York, NY, USA , New York (United States)
  • 4 New York University School of Medicine, Department of Medicine, New York, NY, USA , New York (United States)
  • 5 New York University, Ronald O. Perelman, Department of Dermatology, New York, NY, USA , New York (United States)
  • 6 Massachusetts General Hospital Cancer Center, Harvard Medical School, Center for Melanoma, Boston, MA, USA , Boston (United States)
  • 7 University of California Los Angeles, Division of Hematology-Oncology, Department of Medicine, Los Angeles, CA, USA , Los Angeles (United States)
Type
Published Article
Journal
Cancer Immunology Immunotherapy
Publisher
Springer-Verlag
Publication Date
Mar 12, 2019
Volume
68
Issue
6
Pages
897–905
Identifiers
DOI: 10.1007/s00262-019-02318-8
Source
Springer Nature
Keywords
License
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Abstract

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568—a risk variant for allergy, colitis and type 1 diabetes—was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12–0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.

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