Neoadjuvant rituximab modulates the tumor immune environment in patients with high risk prostate cancer

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 interdependence between Band 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.

B Cell Orchestration of Anti-tumor Immune Responses: A Matter of Cell Localization and Communication

“…On the other hand, corticosteroids, diet, rituximab and chemotherapy can impair the formation of TLS and reduce the development of GCs, potentially blunting anti-tumor immune response ( Liu L. et al, 2017 ; Silina et al, 2018 ; Ryan et al, 2020 ).…”

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 3: PD-L1, Intracellular Signaling Pathways and Tumor Microenvironment

“…PD-L1 and VISTA were upregulated in subsets of post-treatment intratumoral macrophages (CD163 + and ARG1 +, suggesting a M2-like phenotype) and in blood monocytes. High PD-L1 expression was found in CD4+ T cells, CD8+ T cells, and CD68+ macrophages [81], while VISTA may also be expressed by CD8+ cells [30].…”

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 1: Focus on Immunohistochemical Results with Discussion of Pre-Analytical and Interpretation Variables

“…Few studies [15,25,26,28,31,34,40,48] (Table S2) evaluated the PD-L1 expression density by counting the number of PD-L1+ tumor and/or immune cells in variably analyzed areas. Different methods of analysis and scoring were used.…”