Abstract 5023: Immunomodulation of the multi-tyrosine kinase inhibitor TAS-115 in a mouse model of prostate cancer
Authors: Velasco Marco A. De , Kura Yurie , Sato Noriko , Ando Naomi , Sakai Kazuko , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2019

Abstract
Increasingly, immunotherapeutic agents are making their way into the clinic for the management of cancer, however, not all patients respond to single agent treatments. Susceptibility to immunotherapy is highly dependent on a tumor’s immune composition. Agents that are able modulate the tumor’s microenvironment (TME) to improve the balance between cytotoxic T cells and immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs) M2-polarized macrophages and T regulatory cells (Tregs) are highly sought. We previously evaluated the preclinical activity of the multikinase inhibitor TAS-115 on mouse model of prostate cancer and showed that its antitumor effect was due in large part to its influence on the TME. In this study we examine the consequences of TAS-115 administration alone or in combination with androgen withdrawal via surgical castration or anti-androgen therapy with apalutamide, and focus on its influence on antitumor immunity. Pten/Trp53-double knockout mice were treated with TAS-115 alone or in combination with surgical castration or apalutamide for 4 weeks. Overall, TAS-115 reduced prostate tumor burden by 10.5%, however, 37.5% (3/5) of mice experienced no response (7.5%), while reductions of 14% and 27% were observed in 25% (2/8), 37.5% (3/5) of the remaining mice, respectively. A similar trend was noted in mice treated with the TAS/apalutamide combination but TAS plus surgical castration. Changes in cancer cell proliferation and apoptosis were insignificant with TAS-115 treatment, however, 2 of 4 TAS-115-responsive mice used for immunohistochemical (IHC) analysis showed a ~3-fold increased cleaved caspase-3 expression over non responsive mice. All TAS-115-treated mice showed reduced levels of phosphorylated STAT-3. Flow cytometric analysis of dissociated tumor samples revealed a reduction of tumor associated macrophages (TAMs) particularly when TAS-115 was given in combination with castration or apalutamide. Further analysis by IHC and qRT-PCR showed a M2-M1 polarization switch after TAS-115 therapy accompanied with decreased accumulation of monocytic MDSCs. An increase in tumor infiltrating neutrophils was also observed in mice receiving TAS-115. Although overall T cell infiltration was not improved TAS-115, there was an enhanced of activated CD8+ T cells, which was especially evident in responders. However, Treg infiltration was also increased after the administration of TAS-115. Overall our findings suggest that TAS-115 induced the reduction of immunosuppressive MDSCs and TAMs and may have induced an M2-M1 switch to provide a less immunosuppressive tumor microenvironment resulting in improved T cell mediated responses and provides evidence to support further investigation into using molecular targeting agents such TAS-115 as immune-modulators in combination with other immunotherapies to enhance or restore cytotoxic T cell activity.
Citation Format: Marco A. De Velasco, Yurie Kura, Noriko Sato, Naomi Ando, Kazuko Sakai, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Immunomodulation of the multi-tyrosine kinase inhibitor TAS-115 in a mouse model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5023.