Abstract
Background: CD38, a druggable ectoenzyme, is involved in the generation of adenosine, which is implicated in tumour immune evasion. Its expression and role in prostate tumour-infiltrating immune cells (TIICs) have not been elucidated. Objective: To characterise CD38 expression on prostate cancer (PC) epithelial cells and TIICs, and to associate this expression with clinical outcomes. Design, setting, and participants: RNAseq from 159 patients with metastatic castration-resistant prostate cancer (mCRPC) in the International Stand Up To Cancer/Prostate Cancer Foundation (SU2C/PCF) cohort and 171 mCRPC samples taken from 63 patients in the Fred Hutchinson Cancer Research Centre cohort were analysed. CD38 expression was immunohistochemically scored by a validated assay on 51 castration-resistant PC (CRPC) and matching, same-patient castration-sensitive PC (CSPC) biopsies obtained between 2016 and 2018, and was associated with retrospectively collected clinical data. Outcome measurements and statistical analysis: mCRPC transcriptomes were analysed for associations between CD38 expression and gene expression signatures. Multiplex immunofluorescence determined CD38 expression in PC biopsies. Differences in CD38+ TIIC densities between CSPC and CRPC biopsies were analysed using a negative binomial mixed model. Differences in the proportions of CD38+ epithelial cells between non-matched benign prostatic epithelium and PC were compared using Fisher's exact test. Differences in the proportions of biopsies containing CD38+ tumour epithelial cells between matched CSPC and CRPC biopsies were compared by McNemar's test. Univariable and multivariable survival analyses were performed using Cox regression models. Results and limitations: CD38 mRNA expression in mCRPC was most significantly associated with upregulated immune signalling pathways. CD38 mRNA expression was associated with interleukin (IL)-12, IL-23, and IL-27 signalling signatures as well as immunosuppressive adenosine signalling and T cell exhaustion signatures. CD38 protein was frequently expressed on phenotypically diverse TIICs including B cells and myeloid cells, but largely absent from tumour epithelial cells. CD38+ TIIC density increased with progression to CRPC and was independently associated with worse overall survival. Future studies are required to dissect TIIC CD38 function. Conclusions: CD38+ prostate TIICs associate with worse survival and immunosuppressive mechanisms. The role of CD38 in PC progression warrants investigation as insights into its functions may provide rationale for CD38 targeting in lethal PC. Patient summary: CD38 is expressed on the surface of white blood cells surrounding PC cells. These cells may impact PC growth and treatment resistance. Patients with PC with more CD38-expressing white blood cells are more likely to die earlier.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 736-746 |
| Number of pages | 11 |
| Journal | European urology |
| Volume | 79 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2021 |
Funding
Financial disclosures: Johann S. de Bono certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: 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, Wei Yuan, and Johann S. de Bono are all employees of The Institute of Cancer Research (ICR), which has a commercial interest in abiraterone. The ICR operates a Rewards to Inventors scheme through which employees of the ICR may receive financial benefit following commercial licensing. Johann S. de Bono has served on advisory boards and received fees from companies including AstraZeneca, Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech/Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, and Vertex Pharmaceuticals. He is an employee of The ICR, which have received funding or other support for his research work from AstraZeneca, Astellas, Bayer, Cellcentric, Daiichi, Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and Vertex, and which has a commercial interest in abiraterone, PARP inhibition in DNA repair defective cancers, and PI3K/AKT pathway inhibitors (no personal income). He was named as an inventor, with no financial interest, for patent 8,822,438. Johann S. de Bono is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Charles G. Drake has served on advisory boards for AZ Medimmune, Bayer, BMS, Compugen, Ferring, F-Star, Genocea, Janssen, Kleo, Merck, Merck-Serono, Pfizer, Pierre Fabre, Roche/Genentech, Shattuck Labs, Tizona, Urogen, and Werewolf. He is an employee of Johns Hopkins University, which hold the BMS patent. He has stock or financial interest in the following companies: Compugen, Harpoon, Kleo, Tizona, Urogen, and Werewolf. Adam Sharp has received travel support from Sanofi and Roche-Genentech, and speaker honoraria from Astellas Pharma. Niven Mehra has served on advisory boards (compensated and institutional) for Roche, MSD, BMS, Bayer, Astellas, and Janssen; received research support (institutional) from Astellas, Janssen, Pfizer, Roche, and Sanofi Genzyme; and received travel support from Astellas and MSD. Wei Yuan received travel grant from Jilin Huarui Gene Technology Ltd. No relevant conflicts of interest were disclosed by other authors. Funding/Support and role of the sponsor: We acknowledge research funding for this work from Cancer Research UK, Prostate Cancer UK, the Movember Foundation through the London Movember Centre of Excellence (CEO13_2-002), the Prostate Cancer Foundation, The V Foundation for Cancer Research (D2016-022), the UK Department of Health through an Experimental Cancer Medicine Centre (ECMC) grant, and Sanofi Aventis. Professor Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding/Support and role of the sponsor: We acknowledge research funding for this work from Cancer Research UK , Prostate Cancer UK , the Movember Foundation through the London Movember Centre of Excellence ( CEO13_2-002 ), the Prostate Cancer Foundation , The V Foundation for Cancer Research ( D2016-022 ), the UK Department of Health through an Experimental Cancer Medicine Centre (ECMC ) grant, and Sanofi Aventis . Professor Johann de Bono is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
Keywords
- Adenosine pathway
- B lymphocyte
- CD38
- Castration-resistant prostate cancer
- Inflammation
- Myeloid cell
- Plasmacyte
- Prostate cancer
- T cell exhaustion
- Tumour microenvironment
ASJC Scopus subject areas
- Urology
