The tumor immune microenvironment differs between metastatic castrate resistant prostate cancer (CRPC) and hormone sensitive prostate cancer (HSPC).

Abstract

251 Background: Immune checkpoint inhibitors (CPIs) (anti-CTLA4, anti-PD-1/PD-L1 mAbs) have had limited monotherapy activity in prostate cancer (PC) compared to urothelial cancer (UC). Recent biomarker studies revealed molecular features associated w/ better efficacy/resistance to CPIs in UC.1 Here we examined the tumor immune microenvironment (iTME) of hormone naïve/sensitive (HSPC) & castrate resistant prostate (CRPC) specimens from primary & metastatic sites, to determine if parallels to UC molecular correlates exist that will allow us to predict subsets of PC pts who are more likely to benefit from rational combination therapies w/ CPIs. Methods: Tumor FFPE archival tissues (HSPC, n = 98; CRPC, n = 46; Unk, n = 6) were sourced from a Royal Melbourne Hospital cohort of PC patients. Tissues were evaluated by H&E for TILs & IHC performed for PD-L1 (clones SP142 & SP263) & CD8. RNAseq was conducted & Lund bladder molecular subtyping performed during bioinformatics analyses. TCGA PRAD dataset was used for further validation. Results: We first applied Lund molecular subtyping to broadly categorize this cohort into luminal/basal subtypes. CRPC tumors were almost entirely luminal, whereas HSPC tumors were mainly basal. Luminal PC tumors enriched for Wnt gene sets (p = 0.026) & enriched for a genomically unstable (GU) subtype w/ higher expression of DNA damage repair (DDR) & cell cycle gene sets (p = 0.082). Compared to CRPC, HSPCs had higher numbers of infiltrating CD8s (p = 4.37e-004), increased expression of T-effector, MHC-I antigen presentation machinery, immune checkpoints, macrophages & activated stromal biology, including the fibroblast TGFβ response signature. PD-L1 on immune cells by SP142 & SP263 was 30% & 17% respectively & was enriched in HSPC samples (SP142: CRPC 18% vs. HSPC 34%, p = 0.08). Within patients w/ CRPC, differences were minimal between primary & metastatic samples. Conclusions: These analyses on the iTME contexture of PC reveal potentially actionable biological nodes for targeted therapies. These findings could inform future clinical strategies to improve CPI responses in CRPC & HSPC w/ rationale combinations.1. Mariathasan et al. Nature 2018.