Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone

Frontiers in Immunology

Immunology

Takuya Matsumoto¹  Keita Ito¹  Yoshiyuki Manabe²  Koichi Fukase²  Kiyoshi Ando³  Toshiro Seki⁴  Atsushi Yasuda⁴  Shino Ohshima⁵  Daiki Kirigaya⁵  Nagi Katano⁵  Tomoka Shimizu⁵  Soga Yamada⁵  Yusuke Ohno⁶  Yoshie Kametani⁷  Takashi Shiina⁷  Hitoshi Ishimoto⁸  Mikio Mikami⁸  Hirofumi Kashiwagi⁸  Yumiko Goto⁸  Banri Tsuda⁹  Masatoshi Maeki^1,10  Manabu Tokeshi^1,10  Ryoji Ito^1,11 

[1] Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan;Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan;Forefront Research Center, Osaka University, Osaka, Japan;Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan;Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;Department of Internal Medicine, Division of Nephrology, Endocrinology, and Metabolism, Tokai University School of Medicine, Isehara, Japan;Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara, Japan;Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara, Japan;Human Disease Model Laboratory, Department of Applied Research for Laboratory Animals, Central Institute for Experimental Animals, Kawasaki, Japan;Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara, Japan;Institute of Advanced Biosciences, Tokai University, Hiratsuka, Kanagawa, Japan;Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Japan;Department of Palliative Medicine, Tokai University School of Medicine, Isehara, Japan;Faculty of Engineering, Hokkaido University, Sapporo, Japan;Human Disease Model Laboratory, Department of Applied Research for Laboratory Animals, Central Institute for Experimental Animals, Kawasaki, Japan;

关键词: breast cancer;    immune environment;    liposome;    progesterone;    programmed death ligand 1;    humanized mouse;   

DOI  :  10.3389/fimmu.2023.1173728

 received in 2023-02-25, accepted in 2023-06-26,  发布年份 2023

来源: Frontiers

【 摘 要 】

Immune checkpoint inhibitors highlight the importance of anticancer immunity. However, their clinical utility and safety are limited by the low response rates and adverse effects. We focused on progesterone (P4), a hormone produced by the placenta during pregnancy, because it has multiple biological activities related to anticancer and immune regulation effects. P4 has a reversible immune regulatory function distinct from that of the stress hormone cortisol, which may drive irreversible immune suppression that promotes T cell exhaustion and apoptosis in patients with cancer. Because the anticancer effect of P4 is induced at higher than physiological concentrations, we aimed to develop a new anticancer drug by encapsulating P4 in liposomes. In this study, we prepared liposome-encapsulated anti-programmed death ligand 1 (PD-L1) antibody-conjugated P4 (Lipo-anti-PD-L1-P4) and evaluated the effects on the growth of MDA-MB-231 cells, a PD-L1-expressing triple-negative breast cancer cell line, in vitro and in NOG-hIL-4-Tg mice transplanted with human peripheral blood mononuclear cells (humanized mice). Lipo-anti-PD-L1-P4 at physiological concentrations reduced T cell exhaustion and proliferation of MDA-MB-231 in vitro. Humanized mice bearing MDA-MB-231 cells expressing PD-L1 showed suppressed tumor growth and peripheral tissue inflammation. The proportion of B cells and CD4+ T cells decreased, whereas the proportion of CD8+ T cells increased in Lipo-anti-PD-L1-P4-administrated mice spleens and tumor-infiltrated lymphocytes. Our results suggested that Lipo-anti-PD-L1-P4 establishes a systemic anticancer immune environment with minimal toxicity. Thus, the use of P4 as an anticancer drug may represent a new strategy for cancer treatment.

【 授权许可】

Unknown   
Copyright © 2023 Kametani, Ito, Ohshima, Manabe, Ohno, Shimizu, Yamada, Katano, Kirigaya, Ito, Matsumoto, Tsuda, Kashiwagi, Goto, Yasuda, Maeki, Tokeshi, Seki, Fukase, Mikami, Ando, Ishimoto and Shiina