Abstract B91: Tasquinimod targets immuno-suppressive myeloid cell populations and enhances immunotherapy in murine prostate cancer models.

Abstract

Abstract Purpose: A major component of the immunosuppressive environment responsible for immune tolerance in cancer is represented by myeloid cell populations such as myeloid derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs). These cells facilitate carcinogenesis and tumor progression by impairing T and NK cells activation and contributing to modulate angiogenesis. Tasquinimod is an anti-angiogenic and immunomodulatory agent that has shown clinical benefit in patients with prostate cancer. This agent has been found to bind to the inflammatory protein S100A9, to block the interaction of S100A9 with myeloid cells surface receptors, and therefore has the potential to affect accumulation and function of these cells. Experiments and Objectives: We tested tasquinimod in combination with a vaccine therapy in two castration resistant, syngenic transplantable murine prostate cancer models: CR Myc-Cap and TRAMP-C2. This study had the following objectives: 1) to explore tasquinimod's novel immunomodulatory activities and underlining mechanism; 2)To investigate whether tasquinimod inhibits the induction and function of immunosuppressive myeloid cell populations; 3) To assess whether tasquinimod can facilitate vaccine therapy in the castrate resistant prostate cancer models. Results: We observed that the peripheral MDSCs (in blood and spleen) dramatically increased in tumor bearing mice as compared to naïve mice. The MDSCs number increase correlated with disease progression in the transgenic model. Tasquinimod treatment depleted Gr1-CD11b+, Ly6G-CD11b+ (monocytic MDSCs) myeloid cells and M2 macrophages in peripheral sites, and reduced Gr1+CD11b+ MDSCs infiltrates in the tumors. In addition, tasquinimod (10mg/kg) dramatically improved tumor-specific immune responses, including the granzyme B expression in CD8 cells and cytotoxicity of splenocytes, and enhanced anti-tumor activity of a survivin-mimetic peptide vaccine. Conclusions: 1. MDSCs accumulate in prostate cancer models suggesting that MDSCs may contribute to immune tolerance in prostate cancer. 2. Tasquinimod reduces immunosuppressive MDSCs and M2 macrophage and may facilitate vaccine therapy by enhancing cell-mediated cytotoxic tumor cell killing and the anti-tumor immune response. Citation Format: Li Shen, Kiersten Marie Miles, Michael Ciesielski, Leigh Ellis, Robert Fenstermaker, Roberto Pili. Tasquinimod targets immuno-suppressive myeloid cell populations and enhances immunotherapy in murine prostate cancer models. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B91.