Abstract 5068: Nintedanib enhances antitumor effects of anti-PD-1 therapies through inhibition of immunosuppressive cells in tumor microenvironment

Abstract

Abstract Background: Although programmed cell death-1 (PD-1) inhibitors have achieved promising and durable responses in patients with several types of cancer, many patients show intrinsic resistance to PD-1 inhibitors. Extensive studies have demonstrated that immunosuppressive cells are induced in tumor microenvironment and inhibit antitumor effects of PD-1 inhibitors. The aim of current study is to investigate whether nintedanib, which targets multi-tyrosine kinase including vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, reduced immunosuppressive cells in tumor microenvironment and augments antitumor effects of PD-1 inhibitors. Method: Mice were inoculated subcutaneously with CT26 murine colon carcinoma or MC38 murine colon carcinoma and were treated with nintedanib (50 mg/kg), αPD-1mAbs (10 mg/kg) or nintedanib plus αPD-1mAbs. The tumor size was measured in 2 perpendicular dimensions 3 times per week. Types of cells infiltrating into tumors and immune status of tumor-draining lymph nodes were assessed using flow cytometry and immunohistochemistry (IHC). Results: RNA sequencing data revealed that nintedanib decreased gene expression related to endothelial mesenchymal transition, angiogenesis and coagulation. Flow cytometry showed that nintedanib significantly decreased the percentage of myeloid-derived suppressor cells and cancer-associated fibroblast in tumor tissues. Both of flow cytometry and IHC analysis showed that nintedanib significantly increased IFN-ϒ+CD4+ and CD8+ T cells infiltrating in tumors. In addition, nintedanib plus αPD-1mAbs significantly retarded tumor progression. Conclusion: Nintedanib decreased immunosuppressive cells, increased effector T cells, and enhanced anti-tumor effects of αPD-1mAbs. Based on these findings, there are possibility that nintedanib improves clinical outcomes of cancer patients treated with PD-1 inhibitors. Citation Format: Ryo Suzuki, Satoshi Watanabe, Kunihiro Shono, Takaaki Masuda, Tomoki Sekiya, Yuka Goto, Toshiya Fujisaki, Masashi Arita, Aya Ohtsubo, Satoshi Shoji, Tomohiro Tanaka, Koichiro Nozaki, Rie Kondo, Yu Saida, Satoshi Hokari, Riuko Ohashi, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Toshiaki Kikuchi. Nintedanib enhances antitumor effects of anti-PD-1 therapies through inhibition of immunosuppressive cells in tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5068.