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

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...

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Autores principales: Kametani, Yoshie, Ito, Ryoji, Ohshima, Shino, Manabe, Yoshiyuki, Ohno, Yusuke, Shimizu, Tomoka, Yamada, Soga, Katano, Nagi, Kirigaya, Daiki, Ito, Keita, Matsumoto, Takuya, Tsuda, Banri, Kashiwagi, Hirofumi, Goto, Yumiko, Yasuda, Atsushi, Maeki, Masatoshi, Tokeshi, Manabu, Seki, Toshiro, Fukase, Koichi, Mikami, Mikio, Ando, Kiyoshi, Ishimoto, Hitoshi, Shiina, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10364058/
https://www.ncbi.nlm.nih.gov/pubmed/37492571
http://dx.doi.org/10.3389/fimmu.2023.1173728
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author Kametani, Yoshie
Ito, Ryoji
Ohshima, Shino
Manabe, Yoshiyuki
Ohno, Yusuke
Shimizu, Tomoka
Yamada, Soga
Katano, Nagi
Kirigaya, Daiki
Ito, Keita
Matsumoto, Takuya
Tsuda, Banri
Kashiwagi, Hirofumi
Goto, Yumiko
Yasuda, Atsushi
Maeki, Masatoshi
Tokeshi, Manabu
Seki, Toshiro
Fukase, Koichi
Mikami, Mikio
Ando, Kiyoshi
Ishimoto, Hitoshi
Shiina, Takashi
author_facet Kametani, Yoshie
Ito, Ryoji
Ohshima, Shino
Manabe, Yoshiyuki
Ohno, Yusuke
Shimizu, Tomoka
Yamada, Soga
Katano, Nagi
Kirigaya, Daiki
Ito, Keita
Matsumoto, Takuya
Tsuda, Banri
Kashiwagi, Hirofumi
Goto, Yumiko
Yasuda, Atsushi
Maeki, Masatoshi
Tokeshi, Manabu
Seki, Toshiro
Fukase, Koichi
Mikami, Mikio
Ando, Kiyoshi
Ishimoto, Hitoshi
Shiina, Takashi
author_sort Kametani, Yoshie
collection PubMed
description 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.
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spelling pubmed-103640582023-07-25 Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone Kametani, Yoshie Ito, Ryoji Ohshima, Shino Manabe, Yoshiyuki Ohno, Yusuke Shimizu, Tomoka Yamada, Soga Katano, Nagi Kirigaya, Daiki Ito, Keita Matsumoto, Takuya Tsuda, Banri Kashiwagi, Hirofumi Goto, Yumiko Yasuda, Atsushi Maeki, Masatoshi Tokeshi, Manabu Seki, Toshiro Fukase, Koichi Mikami, Mikio Ando, Kiyoshi Ishimoto, Hitoshi Shiina, Takashi Front Immunol Immunology 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. Frontiers Media S.A. 2023-07-10 /pmc/articles/PMC10364058/ /pubmed/37492571 http://dx.doi.org/10.3389/fimmu.2023.1173728 Text en 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 https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Kametani, Yoshie
Ito, Ryoji
Ohshima, Shino
Manabe, Yoshiyuki
Ohno, Yusuke
Shimizu, Tomoka
Yamada, Soga
Katano, Nagi
Kirigaya, Daiki
Ito, Keita
Matsumoto, Takuya
Tsuda, Banri
Kashiwagi, Hirofumi
Goto, Yumiko
Yasuda, Atsushi
Maeki, Masatoshi
Tokeshi, Manabu
Seki, Toshiro
Fukase, Koichi
Mikami, Mikio
Ando, Kiyoshi
Ishimoto, Hitoshi
Shiina, Takashi
Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone
title Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone
title_full Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone
title_fullStr Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone
title_full_unstemmed Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone
title_short Construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone
title_sort construction of the systemic anticancer immune environment in tumour-bearing humanized mouse by using liposome-encapsulated anti-programmed death ligand 1 antibody-conjugated progesterone
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10364058/
https://www.ncbi.nlm.nih.gov/pubmed/37492571
http://dx.doi.org/10.3389/fimmu.2023.1173728
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