Abstract 5610: The multi tyrosine kinase inhibitor TAS-115 promotes innate and adaptive immune responses of androgen deprivation therapy in mouse prostate cancer
Authors: De Velasco Marco A. , Kura Yurie , Ando Naomi , Sako Noriko , Sakai Kazuko , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: September 2020

We previously used a transgenic mouse model of prostate cancer to show that TAS-115, a multi-kinase inhibitor that targets c-MET, VEGF-R, and CSF1-R signal pathways, effectively reduced growth in a subset of prostate tumors. In this setting, TAS-115 decreased tumor burden by reducing tumor neovascularization and promoting anti-tumor immune activity, however, this phenomenon was not observed when co-administered with androgen deprivation therapy (ADT) which is the primary treatment option for men with advanced prostate cancer. We have also shown that androgen withdrawal can promote T cell infiltration, however, antitumor immune responses were hampered most likely by the increased prevalence of immune suppressive cells consisting of tumor associated macrophages (TAMs), myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) induced after ADT. Our previous findings revealed that TAS-115 was able to suppress M2 polarized macrophages and promote the recruitment and activity of tumoricidal neutrophils in castration-naïve tumors. We surmised that pretreatment with TAS-115 could potentiate antitumor immunity of ADT-induced inflammation by decreasing immune suppressive cell activity. In this follow-up study, we demonstrate that one-week treatment with TAS-115 modified the composition of immune cells in intact prostate tumors from Pten/Trp53-deficient conditional knockout mice. Immunophenotyping studies showed that mice treated with TAS-115 had reduced levels of tumor and circulating monocytic-MDSCs (m-MDSC, CD11b+/Ly6C+) and TAMs. Expression levels of genes associated with m-MDSCs and M2 polarized macrophages (Arg1, Csf1r, Il10, Nos2, Adgre1, CD163, Cd68 and Tnf) were also decreased in TAS-115-treated mice. Increases of total and CD355+(CRTAM) CD8 T cells indicating enhanced recruitment and activation were observed in both tumors and blood of TAS-115 treated mice. Sequencing TAS-115 with or without surgical castration was evaluated in transgenic mice bearing Pten/Trp53-deificent prostate tumors. Mice treated for four weeks with TAS-115/ADT sequential therapy showed a 13.5% (P=0.0836) reduction of tumor burden compared to vehicle-treated controls. Notably, mice treated with TAS-115/ADT sequential therapy were characterized with a decrease of monocytic and granulocytic MDSCs in tumors. Moreover, neutrophil mediated antitumor activity was increased in TAS-115 treated mice. We also use phenotyping, gene expression and immunohistochemical studies to show that reducing immunosuppressive immune cells led to increased CD8 T cell recruitment and activation. These findings provide evidence to support that TAS-115 sequenced with ADT has the potential to augment innate and adaptive antitumor immunity in prostate cancer.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Noriko Sako, Kazuko Sakai, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. The multi tyrosine kinase inhibitor TAS-115 promotes innate and adaptive immune responses of androgen deprivation therapy in mouse prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5610.