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Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. METHODS: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by tar...

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Autores principales: Kato, Ryoji, Haratani, Koji, Hayashi, Hidetoshi, Sakai, Kazuko, Sakai, Hitomi, Kawakami, Hisato, Tanaka, Kaoru, Takeda, Masayuki, Yonesaka, Kimio, Nishio, Kazuto, Nakagawa, Kazuhiko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921555/
https://www.ncbi.nlm.nih.gov/pubmed/33299131
http://dx.doi.org/10.1038/s41416-020-01201-z
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author Kato, Ryoji
Haratani, Koji
Hayashi, Hidetoshi
Sakai, Kazuko
Sakai, Hitomi
Kawakami, Hisato
Tanaka, Kaoru
Takeda, Masayuki
Yonesaka, Kimio
Nishio, Kazuto
Nakagawa, Kazuhiko
author_facet Kato, Ryoji
Haratani, Koji
Hayashi, Hidetoshi
Sakai, Kazuko
Sakai, Hitomi
Kawakami, Hisato
Tanaka, Kaoru
Takeda, Masayuki
Yonesaka, Kimio
Nishio, Kazuto
Nakagawa, Kazuhiko
author_sort Kato, Ryoji
collection PubMed
description BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. METHODS: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB). RESULTS: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8(+) T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8(+) T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice. CONCLUSIONS: Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8(+) T cells, with these effects contributing to enhanced antitumour activity in combination with ICB.
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spelling pubmed-79215552021-12-10 Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts Kato, Ryoji Haratani, Koji Hayashi, Hidetoshi Sakai, Kazuko Sakai, Hitomi Kawakami, Hisato Tanaka, Kaoru Takeda, Masayuki Yonesaka, Kimio Nishio, Kazuto Nakagawa, Kazuhiko Br J Cancer Article BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) suppress antitumour immunity, and the tyrosine kinase inhibitor nintedanib has antifibrotic effects. METHODS: We performed a preclinical study to evaluate whether nintedanib might enhance antitumour immunity by targeting CAFs and thereby improve the response to immune checkpoint blockade (ICB). RESULTS: Whereas nintedanib did not suppress the growth of B16-F10 melanoma cells in vitro, it prolonged survival in a syngeneic mouse model of tumour formation by these cells, suggestive of an effect on the TME without direct cytotoxicity. Gene expression profiling indeed showed that nintedanib influenced antitumour immunity and fibrosis. Tumoural infiltration of CD8(+) T cells and granzyme B production were increased by nintedanib, and its antitumour activity was attenuated by antibody-mediated depletion of these cells, indicating that nintedanib suppressed tumour growth in a CD8(+) T cell-dependent manner. Moreover, nintedanib inhibited the proliferation and activation of fibroblasts. Finally, the combination of nintedanib with ICB showed enhanced antitumour efficacy in B16-F10 tumour-bearing mice. CONCLUSIONS: Our results suggest that nintedanib targeted CAFs and thereby attenuated the immunosuppressive nature of the TME and promoted the intratumoural accumulation and activation of CD8(+) T cells, with these effects contributing to enhanced antitumour activity in combination with ICB. Nature Publishing Group UK 2020-12-10 2021-03-02 /pmc/articles/PMC7921555/ /pubmed/33299131 http://dx.doi.org/10.1038/s41416-020-01201-z Text en © The Author(s), under exclusive licence to Cancer Research UK 2020 https://creativecommons.org/licenses/by/4.0/ Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
spellingShingle Article
Kato, Ryoji
Haratani, Koji
Hayashi, Hidetoshi
Sakai, Kazuko
Sakai, Hitomi
Kawakami, Hisato
Tanaka, Kaoru
Takeda, Masayuki
Yonesaka, Kimio
Nishio, Kazuto
Nakagawa, Kazuhiko
Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts
title Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts
title_full Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts
title_fullStr Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts
title_full_unstemmed Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts
title_short Nintedanib promotes antitumour immunity and shows antitumour activity in combination with PD-1 blockade in mice: potential role of cancer-associated fibroblasts
title_sort nintedanib promotes antitumour immunity and shows antitumour activity in combination with pd-1 blockade in mice: potential role of cancer-associated fibroblasts
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921555/
https://www.ncbi.nlm.nih.gov/pubmed/33299131
http://dx.doi.org/10.1038/s41416-020-01201-z
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