HLA associations with immunotherapy related endocrine toxicity.
Authors: Quandt Zoe , Thorball Christian , Middha Pooja , Johnson Douglas Buckner , Bejan Cosmin A , Yao Lydia , Xu Yaomin , Hodel Flavia , Stravodimou Athina , Shearer-Kang Esther , Liu Geoffrey , Aldrich Melinda C , Schoenfeld Adam Jacob , Ziv Elad , Phillips Elizabeth J , Fellay Jacques , Bergmann Ewa A , Chandler G Scott , Balko Justin M , Saha Ashis 
Published: June 2024

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Background: Endocrine immune related adverse events (irAEs), including thyroid dysfunction (ICI-T), diabetes mellitus (ICI-DM) and hypophysitis (ICI-HP), caused by treatment with immune checkpoint inhibitors (ICIs) are largely irreversible and pose a burden to cancer patients. Variation in HLA predisposes to many autoimmune conditions, but data associating endocrine irAEs to HLA types is limited. Methods: We included 6300 patients from multiple centers across the United States, Canada, Europe and Australia who were treated with ICIs for multiple cancer types. The most common endocrine irAE in these patients was ICI-T (806 cases), followed by ICI-HP (163 cases) and ICI-DM (75 cases). Cases of ICI induced adrenal insufficiency were considered to be ICI-HP unless the patient had an elevated ACTH. Patients without the specific irAE were considered controls. Genotyping and HLA imputation were completed at each institution independently. Associations between HLA types and ICI-T, ICI-DM, and ICI-HP were tested in patients of European ancestry after adjustment for type of immunotherapy (PD-1/PD-L1 monotherapy, anti-CTLA-4 monotherapy, and combination), cancer type, sex, age and 5 principal components, at each center. The results were then meta-analyzed using fixed-effects inverse-variance weighted approach. False discovery rate (FDR) adjusted p-value of 0.05 was considered significant whereas those between 0.05 and 0.1 were considered nominally significant. Results: In the ICI-DM group, we identified 1 significant association with HLA DRB1*04:01 (OR=2.45, FDR=0.002) which is known to increase risk for type 1 DM (T1DM) in European ancestry. There were 5 additional nominal associations including DRB1*0301 (OR=2.16, FDR=0.07), a known HLA for T1DM in European ancestry. For ICI-HP, there were 7 significantly associated HLA types. Of particular interest are DRB1*14:01 (OR=3.98, FDR=0.02), DRB1*07:01 (OR=1.86, FDR=0.02) and C*07:02 haplotype (OR=1.79, FDR=0.02). While DR7 and DR14 are novel associations, C*07:02 is in linkage disequilibrium with DR15 and DQB1*06:02, both of which have previously been associated with ICI-HP. For ICI-T, there were no associated HLA types. Conclusions: In our study, we report HLA types associated with endocrine irAEs. In particular, we see HLA associations for ICI-DM that are known to be associated with T1DM. This suggests a potential shared mechanism between these forms of autoimmune DM. Additionally we found novel HLA associations with ICI-HP. These findings may have an impact on the clinical care of patients treated with ICI. However, further work is warranted to determine if HLA typing prior to ICI initiation should be considered for irAE risk prediction, irAE surveillance, irAE prevention, and possibly cancer treatment decisions.