Background: CD38, an ecto-enzyme involved in adenosine synthesis, is implicated in tumor immune evasion. Its expression and role in the prostate tumor microenvironment (TME) has not been fully elucidated. Main objectives: To determine whether CD38 is associated with prostate cancer (PC) immune evasion, to characterize CD38 expression on PC epithelial cells and tumor infiltrating immune cells (TIICs) as tumors progress from castration-sensitive PC (CSPC) to metastatic castration-resistant PC (mCRPC), and to determine the association between CD38+ TIICs and survival.
Methods: Data from 159 mCRPC transcriptomes from the Stand Up To Cancer/Prostate Cancer Foundation cohort were analyzed for associations between CD38 and 200 cell signaling pathways, an adenosine signature and T cell exhaustion signatures. CD38 protein expression on tumor epithelial cells and TIICs was scored using validated immunohistochemistry (IHC) assays on 51 treatment-naïve CSPC biopsies and matching, same-patient mCRPC biopsies obtained between 2016-2018 from men treated at The Royal Marsden Hospital. To characterize CD38+ TIICs, CD38 co-expression with immune cell surface markers for T cells (CD3), B cells (CD19, CD20, CD138, CD79a), and myeloid cells (CD11b, CD15, CD33) was determined by dual-color IHC or multiplex immunofluorescence. The change in CD38+ TIICs density from CSPC to mCRCP was assessed by negative binomial regression and the associations between CD38+ TIIC density and survival were studied using Kaplan-Meier methods, Cox regression and the log-rank test.
Results: Unbiased transcriptome analyses showed that CD38 mRNA expression in mCRPC was associated with upregulated immune signaling pathways, with the ten pathways showing the strongest evidence of association (all P < 1 × 10^-10) with CD38 mRNA expression all being immunomodulatory. CD38 expression was associated with IL-23 signaling (P < 1 × 10^-10), a myeloid suppressor cell-derived mediator of endocrine resistance, as well as immunosuppressive adenosine signaling (P < 1 × 10^-8) and T cell exhaustion signatures (P < 1 × 10^-10). CD38 protein was largely absent from tumor epithelial cells (7.7%). CD38 was expressed by phenotypically diverse TIICs. CD38+ TIICs co-expressed myeloid cell surface markers (CD33, CD15), B cell surface markers (CD19, CD20, CD79a, CD138), and the T cell surface marker (CD3). CD38+ TIIC density increased as tumors progressed from CSPC to CRPC (negative binomial regression, P = 0.03). CSPC and CRPC with higher CD38+ TIIC density (dichotomized based on the median; > 1.5 cells/mm^2) were associated with shorter overall survival from the time of PC diagnosis (hazard ratio [HR]: 1.89; 95% CI: 1.02-3.50) and the time of mCRPC biopsy (HR: 2.14; 95% CI: 1.15-4.00), respectively.
Conclusion: CD38 is expressed by diverse TIICs in the prostate TME and was associated with potential mechanisms of immune evasion. CD38 expression may serve as a potential prognostic biomarker and therapeutic target in PC aimed at overcoming PC immunoresistance.
Citation Format: Christina Guo, Mateus Crespo, Bora Gurel, David Dolling, Jan Rekowski, Adam Sharp, Antonella Petremolo, Semini Sumanasuriya, Daniel N. Rodrigues, Ana Ferreira, Rita Pereira, Ines Figueiredo, Niven Mehra, Maryou B.K. Lambros, Antje Neeb, Veronica Gil, Leon Terstappen, Andrea Alimonti, Charles G. Drake, Wei Yuan, Johann S. de Bono. CD38 in the advanced prostate cancer [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO003.