Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors

BACKGROUND: Immune checkpoint inhibitors (ICIs) have dramatically improved survival in patients with cancer but are often accompanied by severe immune-related adverse events (irAEs), which can sometimes be irreversible. Insulin-dependent diabetes is a rare, but life-altering irAE. Our purpose was to determine whether recurrent somatic or germline mutations are observed in patients who develop insulin-dependent diabetes as an irAE. METHODS: We performed RNA and whole exome sequencing on tumors from 13 patients who developed diabetes due to ICI exposure (ICI-induced diabetes mellitus, ICI-DM) compared with control patients who did not develop diabetes. RESULTS: In tumors from ICI-DM patients, we did not find differences in expression of conventional type 1 diabetes autoantigens, but we did observe significant overexpression of ORM1, PLG, and G6PC, all of which have been implicated in type 1 diabetes or are related to pancreas and islet cell function. Interestingly, we observed a missense mutation in NLRC5 in tumors of 9 of the 13 ICI-DM patients that was not observed in the control patients treated with the same drugs for the same cancers. Germline DNA from the ICI-DM patients was sequenced; all NLRC5 mutations were germline. The prevalence of NLRC5 germline variants was significantly greater than the general population (p=5.98×10(−6)). Although NLRC5 is implicated in development of type 1 diabetes, germline NLRC5 mutations were not found in public databases from patients with type 1 diabetes, suggesting a different mechanism of insulin-dependent diabetes in immunotherapy-treated patients with cancer. CONCLUSIONS: Validation of the NLRC5 mutation as a potential predictive biomarker is warranted, as it might improve patient selection for treatment regimens. Furthermore, this genetic alteration suggests potential mechanisms of islet cell destruction in the setting of checkpoint inhibitor therapy.