Single-agent immunotherapeutic approaches are promising for treating castrate-resistant prostate cancer (CRPC) patients; however, to date no significant improvement in survival has been reported. Mixed response to therapy occurs because metastatic lesions are highly heterogeneous. These lesions exhibit distinct genomic changes that are linked to a tumor microenvironment that is often poorly populated by immune cells. In other tumor types, a high percent genome altered (e.g., aneuploidy) associates with an overall reduction in immune response in the primary tumor microenvironment. However, the association between genomic changes and immune cell composition is poorly understood in metastatic prostate cancers. Thus, we quantified the abundance of 22 immune cell types in 330 tumors from two independent public domain CRPC cohorts and 491 primary prostate tumors from TCGA using the Absolute Mode from CIBERSORT. The estimation in CRPC was performed using whole-transcriptome data from West Coast Dream Team (Abida et al., 2019; n=212) and East Coast Dream Team (Robinson et al., 2015; n=117) samples. We did not identify any significant correlations between mutational load and immune cell abundance in the three investigated cohorts. In primary tumors, aneuploidy was weakly negatively correlated with CD8+ and CD4+ T-cell abundance (R=-0.14 and R=-0.09, P<0.05). Overall, metastatic lesions demonstrated a low absolute abundance of the majority of immune cell subtypes, with higher levels of CD8+ T-cells, memory CD4+ T-cells, macrophages, and plasma cells. We found that bone lesions had the lowest abundance of CD8+ T-cells (Kruskal-Wallis, p=0.05) and the highest abundance of macrophages (P<0.0001) compared to lymph node and liver samples. Overall, aneuploidy was negatively correlated with immune cell abundance in both metastatic cohorts (Spearman correlation, P<0.05). Interestingly, lymph node metastases showed the strongest negative correlation between aneuploidy and T-cell abundance in both West and East cohorts (R=-0.36 and R=-0.32, respectively, p<0.01). Our preliminary results show that the extent of chromosomal aberrations in CRPC is significantly associated with underlying immune cell infiltrates. These results have potential implications for future immunotherapy trials in prostate cancer.

Citation Format: Thiago Vidotto, Daniela C. Salles, Tamara L. Lotan. High aneuploidy levels are linked to a reduced immune-cell abundance in metastatic castrate-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A31.