Immunotherapy can be a highly effective anti-cancer treatment but it can often lead to significant adverse events. The mechanisms of immunotherapy toxicity are poorly understood and no established biomarkers currently exist. In this work, we conducted a genome-wide association study (GWAS) of irAEs in ~1750 patients on immune checkpoint inhibitors at Dana-Farber and identified multiple germline variants associated with moderate to high grade irAEs – the first discovery of germline biomarkers for immunotherapy. These variants were common, had high effects, and replicated in multiple independent cohorts. An association near the IL7 gene implicated novel alternative splicing of IL7, as well as improved survival for melanoma patients not treated with immunotherapy – also a first! The companion paper of Taylor et al. Nat Med, led by the Fairfax lab, conducted a detailed molecular characterization this variant and revealed treatment and cell type specific mechanisms. We believe this study opens the door to much more GWAS discovery for thereapy-related response and toxicity.
For more, see the threads from Stefan Groha and Dr. Choueiri, as well as the News & Views editorial and coverage in Cancer Discovery.
Variant near IL7 associated with splicing/protein expression (a) as well as effects on survival and immunotherapy toxicity (b).