Abstract 3881: Immune profiling of advanced prostate cancer harboring homologous recombination deficiency

Abstract Background: Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects up to 6-8% of patients with localized PCa and up to 30% of patients with metastatic castrate-resistant prostate cancer (mCRPC) and is predictive of response to PARP inhibitors. The potential activity of ICI in this subset of patients is unknown and the tumor microenvironment (TME) associated with HRD is poorly understood. We used PCa tumors of patients with known HRD alterations as a model to study clinically relevant, therapeutically targetable drivers of tumor immunology. Methods: Archival tumor tissue of patients with known germline or somatic HRD alterations enrolled in our institutional GU Biobank (n=13) was used for immunohistochemistry to evaluate the expression of the following immune markers in both tumor cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (A2aR), GAL9, IL-2, LAG3, PD-L2, and TIM-3. The same markers were analyzed in untreated (n=104), neoadjuvant hormone therapy treated (NHT) (n=16), neuroendocrine (NEPC) (n=41) and CRPC (n=22) tissue. Two-tailed t-test and Pearson R correlations were performed for analysis. Results: Among screened HRD alterations,BRCA1/2 were the most frequently identified (BRCA1/2n=6, FANCCn=1, FANCD2=2, PALB2=1, CDK12n=1, ATRn=2). CD8+ cells were primarily localized in the stroma of HRD cohort specimens and were more abundant compared to NEPC (p≤ 0.05) and untreated tumors (p≤0.01). The HRD cohort had higher levels of A2aR, in TC and SL (p≤0 .0001 for both) and higher levels of PD-L2 in TC (p≤0.0001) compared to all other cohorts and in the SL (p≤0.05) compared to untreated, CRPC and NEPC cohorts. Lower levels of LAG3 were found in the HRD cohort TC compared to NHT cohort, and in HRD cohort SL compared to all cohorts (p≤0.0001 for both). There was no difference in TIM-3 or GAL9 expression. Conclusions: Evaluation of stromal and tumor cell immune profiling indicates that compared to other subtypes, PCa with HRD alteration have a unique immune profile abundant in CD8+ cell, and PD-L2 and A2aR expression. Not only does this indicate an immune active TME but also identifies therapeutically actionable immunotherapeutic pathways which may render clinical benefit in this patient population. Citation Format: Maryam Soleimani, Sonia Kung, Neetu Saxena, Ladan Fazli, Lucia Nappi. Immune profiling of advanced prostate cancer harboring homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3881.