Immunogenomic landscape of neuroendocrine prostate cancer (NEPC).

Abstract

224 Background: Prostate cancer (PCa) shows limited clinical benefit from current immunotherapy strategies. NEPC is a histologic subtype of advanced PCa that most often arises clonally from castrate resistant prostate adenocarcinoma (CRPC) as a mechanism of resistance, but shares pathologic, clinical, and molecular features with small cell lung carcinoma (SCLC). We investigated the immune landscape of NEPC in relation to other PCa subtypes and SCLC to identify potential immunological targets. Methods: We evaluated RNA-seq from 190 patients comprising benign prostate (n = 29; 25 PCa matched), localized PCa (n = 68), hormone-naïve metastatic prostate adenocarcinoma (mPCa; n = 11), CRPC (n = 54), NEPC (n = 25) with follow-up data, and SCLC (n = 28) (Rudin et al., Nat Gen 2012). Additionally, 290 patients had WES data available for tumor mutational burden (TMB). Unsupervised clustering of FPKMs was performed to identify an immune rich cluster of 232 genes, which was used to categorize immune status and prioritize validation of select targets by IHC. Results: Median TMB of NEPC was similar to CRPC (38.0 vs 37.0 p= 0.44) but significantly lower than SCLC (38.0 vs 142.5, p< 0.001). Unsupervised assessment of T-cell related gene expression identified a predominantly cold immune status across subtypes, with hot (n = 8) tumors associated with metastatic tumors of the LN and bone. Worse overall survival was seen with intermediate vs cold T-cell immune status (66.5 mo vs 101.5 mo; p < 0.001). Further analysis of NEPC showed lower expression of cytokines ( p< 0.01) and variation in checkpoint markers. Specifically, NEPC had significantly lower expression of PD1 in relation to CRPC ( p= 0.0001) and SCLC ( p = < 0.0001), higher PDL1 than CRPC ( p= 0.05) but comparable with SCLC ( p= 0.93) and lower PDL2 than PCa and SCLC ( p= 0.03; < 0.001, respectively). Conclusions: NEPC is characterized by a relatively ‘cold’ tumor immune microenvironment similar to other metastatic prostate cancer subtypes but higher PDL1 expression comparable to SCLC. The inverse correlation between survival outcome and immune infiltration, as well as the novel expression changes in cytokines and checkpoint markers support further investigation into the immune landscape and potential targets for NEPC.