The Immunogenomic Landscape of Neuroendocrine Prostate Cancer

Purpose: Patients with neuroendocrine prostate cancer (NEPC) are often managed with immunotherapy regimens extrapolated from small cell lung cancer (SCLC). We sought to evaluate the tumor immune landscape of NEPC compared to other prostate cancer types and SCLC. Experimental design: In this retrospective study, a cohort of 170 patients with 230 RNA sequencing and 104 matched whole exome sequencing data were analyzed. Differences in immune and stromal constituents, frequency of genomic alterations, and associations with outcomes were evaluated. Results: In our cohort, 36% of the prostate tumors were identified as CD8+ T-cell inflamed, while the remaining 64% were T-cell depleted. T-cell inflamed tumors were enriched in anti-inflammatory M2 macrophages and exhausted T-cells and associated with shorter overall survival relative to T-cell depleted tumors (HR=2.62, p<0.05). Among all prostate cancer types in the cohort, NEPC was identified to be the most immune depleted, wherein only 9 out of the 36 total NEPC tumors were classified as T-cell inflamed. These inflamed NEPC cases were enriched in interferon gamma signaling and PD-1 signaling compared to other NEPC tumors. Comparison of NEPC with SCLC revealed that NEPC had poor immune content and less mutations compared with SCLC, but expression of checkpoint genes PD-L1 and CTLA-4 was comparable between NEPC and SCLC. Conclusions: NEPC is characterized by a relatively immune-depleted tumor immune microenvironment compared with other primary and metastatic prostate adenocarcinoma except in a minority of cases. These findings may inform development of immunotherapy strategies for patients with advanced prostate cancer.