742P Activation of the WNT signaling pathway correlates with innate resistance to immune checkpoint therapies in clear cell renal cell carcinoma

Abstract

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). However, there are still many patients who do not achieve clinical benefit with these agents, even with positive expression of the programmed death-ligand 1 (PD-L1). Here, we aimed to investigate the immune resistance mechanisms in ccRCC. The genomic data and clinical data of the discovery cohort was obtained from The Cancer Genome Atlas (TCGA). The clinical data for the validation cohort in ccRCC treated with immunotherapy was retrospectively collected from Chinese patients. Whole exome sequencing was performed on tissue from patients with ccRCC in a College of American Pathologists-certified and Clinical Laboratory Improvement Amendments-accredited lab. Activation of WNT signaling was inferred by somatic mutations or somatic copy number alterations in WNT signaling elements, including CTNNB1, APC, AXIN1, AXIN2, CSNK1A, WNT1, WNT2, WNT3, WNT4, WNT6, WNT7, WNT8, WNT9, WNT10, WNT16, GSK3, SMAD3, SMAD4 and BCL9L. Two cohorts were enrolled in this study: the discovery cohort from the TCGA, and the validation cohort from Chinese patients with ccRCC. The frequency of WNT pathway alterations in the TCGA cohort was 25.7%, and which represented mutually exclusive molecular subsets. In the TCGA cohort, activating WNT signaling alterations were associated with shorter median PFS (1.4 vs 3.5 months) and OS (10.2 vs 24.2 months). Mutations predicted to activate the WNT pathway were associated with innate resistance to immune checkpoint blockade in clear cell renal cell carcinoma