Abstract 1023: Release of cancer cells from the prostate tumor microenvironment to promote neoantigen exposure and enhance anti-tumor immune response
Authors: Valkenburg Kenneth C. , Pienta Kenneth J. 
Published: August 2018

Prostate tumors are widely considered to be immunologically silent and resistant to immunotherapy. PCa is widely considered to be an immune desert, with little infiltration of cytotoxic T lymphocytes (CTLs). However, anti-tumor immune responses have been seen in PCa in the right context. We believe we can boost immune response and T cell infiltration into PCa tumors by inhibiting the stromal derived factor 1-CXC chemokine receptor 4 (SDF1-CXCR4) signaling axis and releasing tumor cells from the immune-suppressive bone marrow niche. We have shown that CXCR4 antagonism causes PCa disseminated tumor cells (DTCs) to leave the bone marrow niche and enter the circulation as released circulating tumor cells (CTCs). Our hypothesis is that the release of PCa cells from the tumor microenvironment will enhance chemotherapy-induced cell death and the subsequent presentation of tumor-associated antigens, allowing increased anti-tumor response to immunotherapies. I generated a novel selection-free immunofluorescence-based protocol to confirm this in dissemination models of cancer in mice. After CXCR4 inhibition, I observed an approximate five-fold increase in the number of released CTCs in the blood of mice 24 hours after treatment. Very little research has been performed on the proliferation of CTCs or DTCs, particularly when released from the bone marrow niche. I have been able to mark proliferating cells in blood and bone marrow with EdU and quantify proliferating CTCs. We determined that while released cancer cells are proliferating more than DTCs, the ratio of released proliferating cells is not sufficient to cause a robust response to chemotherapy alone. This led to the hypothesis that released cells could provide an excellent substrate for the immune system. Evidence to support this idea is that we consistently observe the engulfment of CTCs by CD45-positive immune cells from the blood of mice, indicating that immune cells may respond to CTCs but not DTCs. Our approach is unique in that we are using CXCR4 inhibition to release cancer cells into the bloodstream to expose them to immune cells and initiate an immune response via activated CTL infiltration into PCa tumors. We believe this represents an innovative polyvalent autologous vaccine approach as it does not rely on a single antigen to stimulate CTLs, and also relies on each individual patient's cancer cells and immune cells. We have also generated some immunofluorescent protocols to determine the immune composition of circulating cells in relation to CTCs. While we believe that CTLs are responsible for most of the anti-tumor immune response, we are using this opportunity to discover novel immune cell types that may be present before and after therapy. This approach, when combined with classic cancer therapy and immunotherapy, may represent a novel way to boost response to cancer therapies in metastatic PCa.

Citation Format: Kenneth C. Valkenburg, Kenneth J. Pienta. Release of cancer cells from the prostate tumor microenvironment to promote neoantigen exposure and enhance anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1023.