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

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

Publication date: Mar 12, 2019

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.

, Chat, Ferguson, R., Simpson, D., Kazlow, E., Lax, R., Moran, U., Pavlick, A., Frederick, D., Boland, G., Sullivan, R., Ribas, A., Flaherty, K., , Osman, Weber, J., and Kirchhoff, T. Autoimmune genetic risk variants as germline biomarkers of response to melanoma immune-checkpoint inhibition. 21951. 2019 Cancer Immunol Immunother.

Concepts Keywords
Allergy Immune checkpoint
Autoimmune Autoimmunity
Autoimmune Diseases Melanoma
Autoimmunity Cancer treatments
Biomarkers Checkpoint inhibitor
Colitis Immunology
Diabetes Biomarkers
Genetic Immune system
Genome Medical specialties
Germline Clinical medicine
ICI Medicine
IL2 Autoimmune diseases
Loci Outcomes metastatic melanoma
Locus
Melanoma
Modulation
Multiple Testing
SNPs

Semantics

Type Source Name
disease MESH colitis
disease DOID allergy
disease MESH autoimmune diseases
disease MESH allergy
disease MESH autoimmunity
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
gene UNIPROT IL21
gene UNIPROT IL2
disease MESH multiple
gene UNIPROT PDCD1
gene UNIPROT RPL17
disease MESH type 1 diabetes
disease DOID colitis

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