Evidence of genetic susceptibility to immune-related dermatitis in patients with melanoma treated with immune checkpoint inhibitors.

Immune checkpoint inhibitor (ICI)-mediated dermatitis is a common treatment-related adverse event. We conducted single-nucleotide polymorphisms (SNPs)-array genotyping on germline DNA from 744 participants in a phase three adjuvant trial of ipilimumab in melanoma. Logistic regression was used to estimate associations between inherited genetic markers and the occurrence of dermatitis. We also tested previously reported dermatitis-related polygenic risk scores (PRS) adjusting for genetic ancestry. Dermatitis of any grade occurred in 52% (232 Gr1, 97 Gr2, and 52 Gr3). We identified two SNPs associated with dermatitis and subsequently developed a two-SNP PRS that was associated with dermatitis risk and severity. Both variants mapped to intronic regions of the insulin-like growth factor 1 receptor and A-kinase anchoring protein 12 genes, which have important roles in immune regulation and inflammatory response. Separately, 11 previously reported dermatitis-related PRSs derived from general population cohorts not exposed to immunotherapy were tested and none was associated with ICI-mediated dermatitis in our cohort. The cohort-derived PRS showed modest discrimination for dermatitis risk (AUC 0.63). The incidence of dermatitis was associated with improved outcomes; patients with grade 1-2 or any-grade dermatitis demonstrated improved relapse-free survival (RFS) (hazard ratio: 0.74; P = 0.007 and 0.77, P = 0.01, respectively). The cohort-derived PRS showed a trend toward improved RFS and overall survival. In conclusion, we generated a novel PRS associated with ICI-mediated dermatitis risk and severity that demonstrated a trend towards improved survival outcomes. Our findings support a role for inherited genetic variation in relation to ICI dermatitis and warrant further investigation.