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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...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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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. |
format | Online Article Text |
id | pubmed-8298272 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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