Background: Androgen deprivation therapy (ADT)-induced immunosuppression has been described in animal models as contributing to castration-resistant prostate cancer (CRPC) development, but the clinical relevance of these observations has not been established. In this study, we compared the immune tumor microenvironment (iTME) of primary prostate cancer (PPC) versus metastatic CRPC (mCRPC). Methods: Genomic and clinically annotated data were obtained of PPC and mCRPC from the TCGA provisional and SU2C/PCF databases. Patients without RNA-seq data were excluded. 22 iTME cell subsets were estimated using CIBERSORT LM22 algorithm. Relative cell proportions and gene expression in log-transformed FPKM were compared using Wilcoxon tests. Results: 499 PPC and 118 mCRPC were studied. Compared to PPC, mCRPC had higher percentage of M2 macrophages (24.6% vs. 10.2%, p<0.0001). High M2 in mCRPC was associated with 2.5-, 6- and 19.5-fold increases in IL-10, VEGFA and ARG1 mRNA levels, respectively (p<0.0001). T- cell exhaustion markers, LAG3 and CD160, were upregulated in mCRPC by 43.2% and 266.7% (p<0.0001). Although CD8 T-cells were higher in mCRPC, the CD8/M2 ratio was lower (1.1 vs. 1.5, p=0.002). Prior use of abiraterone or enzalutamide in the mCRPC cohort (n=54) did not alter iTME cell fractions compared to AR antagonist naïve mCRPC. The detailed iTME comparisons were listed in Table. Conclusions: Our data indicate the development of tumor-favoring iTME in the course of progression to mCRPC while on ADT. The iTME is characterized by increased M2 macrophage infiltration that may provide a novel and important therapeutic target.

*P<0.05 Abbreviation: N, naïve; M, memory; R, resting; A, activated