Germline immunomodulatory expression quantitative trait loci (ieQTLs) associated with immune-related toxicity from checkpoint inhibition

Background: Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI). Methods: We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multi -in-stitutional collaboration. We tested the association of ieQTLs with irAEs in a discovery co-hort of 95 patients, followed by validation in an additional 97 patients. Results: We found that the alternate allele of rs7036417, a variant linked to increased ex-pression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity [odds ratio (OR) = 7.46; 95% confidence interval (CI) = 2.65-21.03; p = 1.43E-04]. This variant was not associated with response (OR = 0.90; 95% CI = 0.37-2.21; p = 0.82). Conclusion: We report that rs7036417 is associated with increased risk of severe irAEs, in-dependent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion, and in-creased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK overexpression in irAE development. These findings support the hypothesis that inherited variation in immune -re-lated pathways modulates ICI toxicity and suggests SYK as a possible future target for therapies to reduce irAEs. & COPY; 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

The rs7036417 mutation linked to increased expression of SYK was associated with an increased risk of severe irAEs in melanoma patients treated with anti-CTLA-4 antibody ipilimumab.