Immunomodulatory effect of cucumarioside A2-2 on macrophage polarization for effective cancer immunotherapy

Wen-Han Chuang(莊雯涵)1, Evgeny Pislyagin2, Dmitry Aminin2*, Yun-Ming Wang1*

1 Department of Biological Science and Technology, National Yang Ming Chiao Tung University

2 G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch, Russian Academy of Science, 159, Pr. 100 let Vladivostoku, 690022 Vladivostok, Russia

Despite intensive developments of adoptive T cell and NK cell therapies, the efficacy against solid tumors remains elusive. Our study demonstrates that macrophage-based cell therapy could be a potent therapeutic option against solid tumors. To achieve this goal, we investigated the effect of a natural triterpene glycoside, cucumarioside A2-2 (CA2-2), on the polarization of mouse macrophages into the M1 phenotype, and explored the antitumor activity of the polarized macrophage. Incubation of murine macrophages with CA2-2 led to polarization into the M1 phenotype, and the CA2-2-pretreated macrophages could selectively target and kill various types of cancer in vitro. Notably, loading near-infrared (NIR) fluorochrome-labeled nanoparticles, MnMEIO-mPEG-CyTE777, into macrophages substantiated that M1 macrophages can target and penetrate tumor tissues in vivo efficiently. Moreover, CA2-2-polarized M1 macrophages significantly attenuated tumor growth and prolonged mice survival in the syngeneic and xenograft mouse models. Therefore, ex vivo CA2-2 activation of mouse macrophages can serve as a useful model for subsequent antitumor cellular immunotherapy developments.