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Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma

Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develo...

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Autores principales: Fu, Yuyin, Peng, Yujia, Zhao, Shengyan, Mou, Jun, Zeng, Lishi, Jiang, Xiaohua, Yang, Chengli, Huang, Cheng, Li, Yuyan, Lu, Yin, Wu, Mengdan, Yang, Yanfang, Kong, Ting, Lai, Qinhuai, Wu, Yangping, Yao, Yuqin, Wang, Yuxi, Gou, Lantu, Yang, Jinliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298272/
https://www.ncbi.nlm.nih.gov/pubmed/34307367
http://dx.doi.org/10.3389/fcell.2021.689727
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author Fu, Yuyin
Peng, Yujia
Zhao, Shengyan
Mou, Jun
Zeng, Lishi
Jiang, Xiaohua
Yang, Chengli
Huang, Cheng
Li, Yuyan
Lu, Yin
Wu, Mengdan
Yang, Yanfang
Kong, Ting
Lai, Qinhuai
Wu, Yangping
Yao, Yuqin
Wang, Yuxi
Gou, Lantu
Yang, Jinliang
author_facet Fu, Yuyin
Peng, Yujia
Zhao, Shengyan
Mou, Jun
Zeng, Lishi
Jiang, Xiaohua
Yang, Chengli
Huang, Cheng
Li, Yuyan
Lu, Yin
Wu, Mengdan
Yang, Yanfang
Kong, Ting
Lai, Qinhuai
Wu, Yangping
Yao, Yuqin
Wang, Yuxi
Gou, Lantu
Yang, Jinliang
author_sort Fu, Yuyin
collection PubMed
description Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody. The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor. Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy.
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spelling pubmed-82982722021-07-24 Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma Fu, Yuyin Peng, Yujia Zhao, Shengyan Mou, Jun Zeng, Lishi Jiang, Xiaohua Yang, Chengli Huang, Cheng Li, Yuyan Lu, Yin Wu, Mengdan Yang, Yanfang Kong, Ting Lai, Qinhuai Wu, Yangping Yao, Yuqin Wang, Yuxi Gou, Lantu Yang, Jinliang Front Cell Dev Biol Cell and Developmental Biology Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody. The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor. Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy. Frontiers Media S.A. 2021-07-08 /pmc/articles/PMC8298272/ /pubmed/34307367 http://dx.doi.org/10.3389/fcell.2021.689727 Text en Copyright © 2021 Fu, Peng, Zhao, Mou, Zeng, Jiang, Yang, Huang, Li, Lu, Wu, Yang, Kong, Lai, Wu, Yao, Wang, Gou and Yang. 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 Cell and Developmental Biology
Fu, Yuyin
Peng, Yujia
Zhao, Shengyan
Mou, Jun
Zeng, Lishi
Jiang, Xiaohua
Yang, Chengli
Huang, Cheng
Li, Yuyan
Lu, Yin
Wu, Mengdan
Yang, Yanfang
Kong, Ting
Lai, Qinhuai
Wu, Yangping
Yao, Yuqin
Wang, Yuxi
Gou, Lantu
Yang, Jinliang
Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma
title Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma
title_full Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma
title_fullStr Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma
title_full_unstemmed Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma
title_short Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma
title_sort combination foretinib and anti-pd-1 antibody immunotherapy for colorectal carcinoma
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298272/
https://www.ncbi.nlm.nih.gov/pubmed/34307367
http://dx.doi.org/10.3389/fcell.2021.689727
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