Abstract 439: BCL-2 inhibitor APG-2575 promotes anti-tumor efficacy of immune checkpoint blockade through converting tumor-associated macrophages into M1 phenotype in non-small cell lung cancer

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Abstract BCL-2 inhibitor APG-2575 promotes anti-tumor efficacy of immune checkpoint blockade through converting tumor-associated macrophages into M1 phenotype in non-small cell lung cancer Background: Immune checkpoint inhibitors (ICIs) has received approval due to its encouraging clinical efficacy with improving the outcome of cancer patients. However, current immunotherapeutic regimens benefit merely a minority of populations. Thus, combining ICIs with other potential modalities is of great significance to enhance the response of single drug alone. Modifying tumor-associated macrophages (TAMs) strategies have attracted attention for ameliorating tumor immunosuppression and improving anti-tumor immunity. Here we exhibit APG2575, a proven BCL-2 inhibitor, can act as an antitumor immune modulator that resets TAMs from M2 to pro-tumoral M1 phenotype and further augment immunotherapeutic efficacy. Methods: By applying non-small cell lung cancer cell lines and murine syngeneic tumor xenograft, we investigated the effects of combined APG-2575 and PD-1 antibody on tumor growth. Furthermore, we explored the role of APG-2575 in regulating TAMs polarization through utilizing human and murine macrophages, involving immortalized and primary models. Besides, IL-10 secretion in cell culture supernatants was detected via ELISA assay. In addition, we also assessed the tumor immune microenvironment regulation of APG-2575 using flow cytometry. Results: In vitro, APG-2575, a BCL-2 inhibitor, augmented the tumor cell lysis induced by T cells when combined with ICIs. Moreover, mice treated with APG-2575 and ICIs showed remarkable tumor regression and prolonging survival which were associated with the increase of granzyme-B, IFN-γ and TNF-α release of CD8+ cytotoxic lymphocytes. Importantly, we found that APG-2575-mediated antitumor T cell immunity is dependent on macrophages. Furthermore, we discovered APG-2575 could induce M2 macrophage switching to M1 phenotype and suppress IL-10 secretion in vitro. Meanwhile, reduced M2 macrophages as well as increased M1 polarization were also observed in the tumor-infiltrating immune cells from mice treated with APG-2575. Additionally, APG-2575-mediated macrophage transition could improve tumor immunosuppression, with decreasing number of myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells in tumor microenvironment. Conclusions: Our data demonstrate that APG-2575 can synergizes with ICIs in vitro and in vivo, which was involved in switching TAMs from M2 to M1 polarization and further improving tumor immunosuppression, finally enhancing T cell anti-tumor activity. These results warranted future clinical evaluation of combination therapy of APG-2575 and ICIs. Key words: BCL-2, APG-2575, ICIs, macrophages, non-small cell lung cancer Citation Format: Fan Luo, Fei Teng Lu, Miao Zhen Qiu, Wen Tao Pan, Lin Zhang, Hong Yun Zhao, Li Zhang, Da Jun yang. BCL-2 inhibitor APG-2575 promotes anti-tumor efficacy of immune checkpoint blockade through converting tumor-associated macrophages into M1 phenotype in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 439.