Abstract 619P
Background
Most patients with metastatic prostate cancer (mPCa) do not derive benefit from immune checkpoint inhibitors (ICI). Homologous recombination deficiency (HRD) affects 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 tumour microenvironment (TME) associated with HRD is poorly understood. We used mPCa tumours of patients with known HRD as a model to study potential clinically relevant, therapeutically targetable drivers of tumour immunology.
Methods
Archival tumor tissue of patients with known germline HRD enrolled in our GU Biobank (n=26) was used for immunohistochemistry (IHC) to evaluate the expression of the following immune markers in both tumour cells (TC) and stromal lymphocytes (SL): CD8, adenosine receptor 2a (AR2a), GAL9, IL-2, LAG3, PDL2, 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 the analysis.
Results
Among the screened HRD genes (ATM, TP53, FANCF, CDK12, CDKN2A, FANCC, ERCC2, PALB2, and BRCA1/2) BRCA1/2 were the most frequently abnormal (17/26). CD8+ cells were primarily localized in the stroma of HRD cohort specimens and were more abundant compared to NEPC (p≤ 0.05) and untreated tumours (p≤0.01). The HRD cohort had significantly higher levels of AR2a, both 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 TIM3 or GAL9 expression.
Conclusions
Evaluation of TC and SL immune profiling indicates that compared to other advanced prostate cancer subtypes, HRD mPCa have a unique immune profile abundant in CD8+ cell, PD-L2 and A2aR expression. Not only does this indicate an immune active TME compared to the historically cold PCa data, but also identifies therapeutically actionable pathways which may render clinical benefit.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
M. Soleimani: Financial Interests, Personal, Other, Honorarium: Pfizer Canada; Financial Interests, Institutional, Research Grant: Abbvie Pharmaceuticals; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Bayer. L. Nappi: Financial Interests, Personal, Other, honorarium: Ipsen Biopharmaceuticals Inc; Financial Interests, Personal, Other, honorarium: Bayer Healthcare Pharmaceuticals. All other authors have declared no conflicts of interest.