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Cancer Immunol Immunother. 2019 Jun;68(6):897-905. doi: 10.1007/s00262-019-02318-8. Epub 2019 Mar 12.

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

Chat V1,2,3, Ferguson R1,2,3, Simpson D1,2,3, Kazlow E1,2,3, Lax R1,2,3, Moran U1,3,4,5, Pavlick A3,4, Frederick D6, Boland G6, Sullivan R6, Ribas A7, Flaherty K6, Osman I1,3,4,5, Weber J1,3,4, Kirchhoff T8,9,10.

Author information

1
Laura and Issac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY, 10016, USA.
2
Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA.
3
The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA.
4
Department of Medicine, New York University School of Medicine, New York, NY, USA.
5
Ronald O. Perelman, Department of Dermatology, New York University, New York, NY, USA.
6
Center for Melanoma, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
7
Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
8
Laura and Issac Perlmutter Cancer Center, New York University School of Medicine, 522 First Avenue, New York, NY, 10016, USA. tomas.kirchhoff@nyumc.org.
9
Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, NY, USA. tomas.kirchhoff@nyumc.org.
10
The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, NY, USA. tomas.kirchhoff@nyumc.org.

Abstract

Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, >ā€‰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 >ā€‰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; pā€‰=ā€‰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.

KEYWORDS:

Autoimmunity; Germline variants; Immune-checkpoint inhibition; Melanoma

PMID:
30863922
PMCID:
PMC6531317
[Available on 2020-06-01]
DOI:
10.1007/s00262-019-02318-8
[Indexed for MEDLINE]

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