LAUSR

Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 and CTLA4 are effective treatments in multiple cancer types, but durable responses are seen only in a minority of patients. Resistance to ICI is likely to reflect a combination of tumor-intrinsic, such as tumor mutational burden, and tumor-extrinsic factors, such as systemic immune suppression and host genetics. With the advent of large-scale germline genotyping studies, there is emerging evidence that host-specific genetic factors can substantially modify both disease risk and responsiveness to therapy. There has been limited characterization to date of the interaction between host genetics and response to ICI. Here, we perform harmonized mutation calling in available normal exome sequencing from 668 metastatic cancer patients treated with ICI (derived from n=7 studies, spanning n=3 cancer types and PD-1/PD-L1/CTLA4-directed therapy) and performed exome-wide association studies in European ancestry patients. For each cancer type (melanoma, renal cell carcinoma, urothelial carcinoma), we conducted exome-wide Cox regression (with PC1-4 and sex as covariates) to identify coding single-nucleotide polymorphisms (SNPs) associated with overall survival (OS). On fixed-effect meta-analysis, we identified a single coding variant (rs140221307, C allele, MAF 0.5% in European populations) that met genome-wide significance (p=1.11 × 10−15, HR=4.86, 95% CI 3.30-7.15). This SNP causes a substitution of Trp to Arg at amino acid 320 at the interface between the transmembrane and extracellular domains of interleukin 17 receptor A (IL17RA). While the secretion mechanism is uncharacterized, soluble IL17RA can be readily detected in plasma and the survival-reducing variant is associated with substantially elevated plasma IL17RA (p=1.90 × 10−9, beta=1.01, Sun et al. 2018) as well as reduced monocyte counts in UK Biobank (p=2.20 × 10−308, beta=-0.60). We have established a prime editing strategy to induce this variant in cultured human monocytes to investigate its biochemical and functional consequences, and are performing validation studies in independent patient cohorts. Soluble IL17RA would be expected to function as a decoy receptor to antagonize IL17/IL17RA signaling, and so these data suggest that activation of IL-17 receptor signaling might improve responsiveness to ICI therapy. Citation Format: Sam O. Kleeman, Michael Chan, Matthew Chvasta, Tobias Janowitz. Exome-wide association study identifies coding variant in IL17RA associated with survival in cancer patients treated with immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5226.