Abstract B180: TAS-115 attenuates tumor-associated macrophages and enhances sensitivity to anti-PD-1 monoclonal antibody in syngeneic mouse tumors
Authors: Haruma Tomonori , Fujita Hidenori , Yamada Yukari , Fukaya Satoshi , Hashimoto Akihiro , Harada Takafumi , Suzuki Takamasa , Matsuo Kenichi , Utsugi Teruhiro , Iwasawa Yoshikazu 
Published: August 2018

Abstract
Background: Clinical efficacy of anti-PD-1 monoclonal antibody (mAb) has been established in various types of cancers. On the other hand, many patients remain unresponsive to anti-PD-1 mAb. Therefore, improvement in clinical response of anti-PD-1 mAb by using suitable combinational therapies and/or optimal methods for patient selection is needed. TAS-115 is a small molecular inhibitor of receptor tyrosine kinases (RTKs) such as the VEGFRs, MET, PDGFRs and CSF1R. Since these RTKs are reported to be involved in the cross talk between tumor micro-environment and immune system, we proposed that TAS-115 may strengthen the efficacy of anti-PD-1 mAb by influencing the immune system in the tumor micro-environment. In this report, we have examined whether TAS-115 could enhance the antitumor efficacy of anti-PD-1 mAb in mouse syngeneic tumors. Global analysis of immune cells was performed to explore the mechanisms for the interaction of TAS-115 and anti-PD-1 mAb. Material and Methods: MC38 (mouse colon carcinoma) was used as an anti-PD-1 mAb sensitive model, and EMT6 (mouse breast carcinoma) was used as an insensitive model to anti-PD-1 mAb. We investigated efficacy of TAS-115 alone and/or in combination with anti-PD-1 mAb in these mouse subcutaneous implanted syngeneic tumor models. In addition, by flow cytometric methods, global analysis of immune cells was done with tumor infiltrated leukocytes (TILs), spleen, tumor-draining lymph node and blood to investigate the effect of TAS-115 on antitumor immunity. Results: In the MC38 model, TAS-115 markedly suppressed tumor growth and increased the efficacy of anti-PD-1 mAb. In the EMT6 model, significant antitumor efficacy of TAS-115 was observed. Analysis of immune cells showed remarkable inhibition by TAS-115 in the ratio of tumor associated macrophages (TAMs) in both MC38 and EMT6 models. Effects of combination therapy of anti-PD-1 mAb with TAS-115 on TAMs and CD8+ T cells were also analyzed in the MC38 model. In the case of combination therapy, we found a decrease in the ratio of TAMs while there was an increase in the ratio of CD8+ T cells in TILs. Discussion: TAMs are considered as one of the major suppressive factors in tumor immunity and are thought to play an important role in resistance to anti-PD-1 mAb. Several kinds of RTKs are known to be involved in survival, proliferation and functions in TAMs. In particular, CSF1R plays major and important role in M2 macrophages regarded as potent suppressors of tumor immunity. Therefore, inhibition of these RTKs by TAS-115 may contribute to the decline of TAMs. As shown by the data reported here, the decrease of TAMs by TAS-115 may be involved in the antitumor efficacy and the enhancement of efficacy of anti-PD-1 mAb. Conclusion: TAS-115 attenuated tumor growth and TAMs in both anti-PD-1 mAb-sensitive and -insensitive mouse syngeneic tumor models. In addition, TAS-115 enhanced the antitumor efficacy of anti-PD-1 mAb. Therefore, TAS-115 may prove to be a useful adjunct to anti-PD-1 mAb.
Citation Format: Tomonori Haruma, Hidenori Fujita, Yukari Yamada, Satoshi Fukaya, Akihiro Hashimoto, Takafumi Harada, Takamasa Suzuki, Kenichi Matsuo, Teruhiro Utsugi, Yoshikazu Iwasawa. TAS-115 attenuates tumor-associated macrophages and enhances sensitivity to anti-PD-1 monoclonal antibody in syngeneic mouse tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B180.