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

• Published in: Cancer Immunology, Immunotherapy Vol. 68; no. 6; pp. 897 - 905
• Main Authors: Chat, Vylyny, Ferguson, Robert, Simpson, Danny, Kazlow, Esther, Lax, Rebecca, Moran, Una, Pavlick, Anna, Frederick, Dennie, Boland, Genevieve, Sullivan, Ryan, Ribas, Antoni, Flaherty, Keith, Osman, Iman, Weber, Jeffrey, Kirchhoff, Tomas
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2019; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Allergies; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Autoimmune diseases; Autoimmune Diseases - genetics; Autoimmune Diseases - immunology; Autoimmune Diseases - therapy; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Cancer Research; Colitis; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; Diabetes mellitus; Diabetes mellitus (insulin dependent); Female; Gene mapping; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genomes; Germ Cells - immunology; Germ Cells - metabolism; Humans; Immune checkpoint inhibitors; Immunology; Immunotherapy - methods; Interleukin 2; Interleukin 21; Interleukin-2 - genetics; Interleukins - genetics; Male; Medicine; Medicine & Public Health; Melanoma; Melanoma - genetics; Melanoma - immunology; Melanoma - therapy; Metastases; Metastasis; Middle Aged; Oncology; Original Article; Patients; PD-1 protein; Polymorphism, Single Nucleotide - genetics; Polymorphism, Single Nucleotide - immunology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Risk Factors; Single-nucleotide polymorphism; Autoimmunity; Germline variants; Immune-checkpoint inhibition; Melanoma
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-019-02318-8

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.