Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer
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Journal of Translational Medicine Open Access
RESEARCH
Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer Stephen T. Ryan1, Jing Zhang3, Danielle N. Burner1, Michael Liss7, Emily Pittman3, Michelle Muldong1, Ahmed Shabaik2, Jason Woo1, Nicole Basler1, Jonathan Cunha1, Shabnam Shalapour3, Monica V. Estrada8, Michael Karin3,4, Karen Messer3,6, Stephen Howell3,5, Christopher J. Kane1,3 and Christina A. M. Jamieson1,3*
Abstract Background: Immunotherapeutic regulation of the tumor microenvironment in prostate cancer patients is not understood. Most antibody immunotherapies have not succeeded in prostate cancer. We showed previously that high-risk PCa patients have a higher density of tumor infiltrating B-cells in prostatectomy specimens. In mouse models, anti-CD20 antibody ablation of B-cells delayed PCa regrowth post-treatment. We sought to determine whether neoadjuvant anti-CD20 immunotherapy with rituximab could reduce CD20+ B cell infiltration of prostate tumors in patients. Methods: An open label, single arm clinical trial enrolled eight high-risk PCa patients to receive one cycle of neoadjuvant rituximab prior to prostatectomy. Eleven clinical specimens with similar characteristics were selected as controls. Treated and control samples were concurrently stained for CD20 and digitally scanned in a blinded fashion. A new method of digital image quantification of lymphocytes was applied to prostatectomy sections of treated and control cases. CD20 density was quantified by a deconvolution algorithm in pathologist-marked tumor and adjacent regions. Statistical significance was assessed by one sided Welch’s t-test, at 0.05 level using a gatekeeper strategy. Secondary outcomes included CD3+ T-cell and PD-L1 densities. Results: Mean CD20 density in the tumor regions of the treated group was significantly lower than the control group (p = 0.02). Mean CD3 density in the tumors was significantly decreased in the treated group (p = 0.01). CD20, CD3 and PD-L1 staining primarily occurred in tertiary lymphoid structures (TLS). Neoadjuvant rituximab was well-tolerated and decreased B-cell and T-cell density within high-risk PCa tumors compared to controls. Conclusions: This is the first study to treat patients prior to surgical prostate removal with an immunotherapy that targets B-cells. Rituximab treatment reduced tumor infiltrating B and T-cell density especially in TLSs, thus, demonstrating inter-dependence between B- and T-cells in prostate cancer and that Rituximab can modify the immune environment in prostate tumors. Future studies will determine who may benefit from using rituximab to improve their immune response against prostate cancer.
*Correspondence: [email protected] 1 Department of Urology, UCSD Moores Cancer Center, University of California San Diego School of Medicine, 3855 Health Sciences Drive, Mail Code: 0987, La Jolla, CA 92093‑0987, USA Full list of author information is available at the end of the article © The Author(s) 2020. This artic
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