Brian D. Lehmann

The Impact of JAK1 Pathogenic Variants and MHC-I Expression on Response to Immune Checkpoint Inhibition in Endometrial Cancer

Abstract Purpose: Immune checkpoint inhibitors (ICI) have increasing application in endometrial cancer, underscoring the need for robust biomarkers for patient selection. JAK1 pathogenic variants (PV) have previously been implicated in immune evasion. In this study, we identify biomarkers predictive of ICI response in endometrial cancer and the implications of JAK1 PVs in this context. Experimental Design: This is a translational study of tumors from 84 patients with endometrial cancer treated with ICIs. High-throughput proteomic-based profiling was used to quantify 193 phosphoprotein/protein expression levels, including key JAK/STAT signaling pathway components. Associations with clinical outcomes were assessed using multivariate regression analysis. The functional consequences of JAK1 PVs were explored through in vitro signaling assays and analyses of The Cancer Genome Atlas database. Results: MHC-I expression correlated with improved progression-free survival (P = 0.035), validated in orthogonal approaches. Notably, a subset of patients harboring JAK1 PVs demonstrated exceptional survival on ICIs. In The Cancer Genome Atlas cohort of microsatellite instability–high and DNA polymerase epsilon–mutated tumors, homozygous loss of JAK1 trended toward decreased survival, whereas heterozygous loss of JAK1 was associated with significantly improved survival (P = 0.026), suggesting partial retention of antigen presentation pathways. Among our ICI-treated microsatellite instability–high tumor samples, NK cell marker NCAM1 was associated with improved survival (P = 0.02). Conclusions: These data support MHC-I as a potential predictive biomarker for ICI response in endometrial cancer. Additionally, we show that partial retention of JAK1 signaling in JAK1 tumors with heterozygous loss is associated with improved survival, potentially attributable to enhanced NK cell activity in tumors with low MHC-I expression.