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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-07-01
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| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.689727/full |
| _version_ | 1819130238488018944 |
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| author | Yuyin Fu Yujia Peng Shengyan Zhao Jun Mou Lishi Zeng Xiaohua Jiang Chengli Yang Cheng Huang Yuyan Li Yin Lu Mengdan Wu Yanfang Yang Ting Kong Qinhuai Lai Yangping Wu Yuqin Yao Yuxi Wang Lantu Gou Jinliang Yang |
| author_facet | Yuyin Fu Yujia Peng Shengyan Zhao Jun Mou Lishi Zeng Xiaohua Jiang Chengli Yang Cheng Huang Yuyan Li Yin Lu Mengdan Wu Yanfang Yang Ting Kong Qinhuai Lai Yangping Wu Yuqin Yao Yuxi Wang Lantu Gou Jinliang Yang |
| author_sort | Yuyin Fu |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-22T08:56:26Z |
| format | Article |
| id | doaj.art-af80427af630405f8fdf9bb3cf41fcd4 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-22T08:56:26Z |
| publishDate | 2021-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-af80427af630405f8fdf9bb3cf41fcd42022-12-21T18:31:50ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-07-01910.3389/fcell.2021.689727689727Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal CarcinomaYuyin Fu0Yujia Peng1Shengyan Zhao2Jun Mou3Lishi Zeng4Xiaohua Jiang5Chengli Yang6Cheng Huang7Yuyan Li8Yin Lu9Mengdan Wu10Yanfang Yang11Ting Kong12Qinhuai Lai13Yangping Wu14Yuqin Yao15Yuxi Wang16Lantu Gou17Jinliang Yang18State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Infectious Diseases and Vaccine, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaDepartment of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, ChinaWest China School of Public Health and Healthy Food Evaluation Research Center/No. 4 West China Teaching Hospital, Sichuan University, Chengdu, ChinaDepartment of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaState Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaImmune 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.https://www.frontiersin.org/articles/10.3389/fcell.2021.689727/fullforetinibanti-PD-1combination therapyimmunotherapytumor microenvironmentcolon cancer |
| spellingShingle | Yuyin Fu Yujia Peng Shengyan Zhao Jun Mou Lishi Zeng Xiaohua Jiang Chengli Yang Cheng Huang Yuyan Li Yin Lu Mengdan Wu Yanfang Yang Ting Kong Qinhuai Lai Yangping Wu Yuqin Yao Yuxi Wang Lantu Gou Jinliang Yang Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma Frontiers in Cell and Developmental Biology foretinib anti-PD-1 combination therapy immunotherapy tumor microenvironment colon cancer |
| 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 | foretinib anti-PD-1 combination therapy immunotherapy tumor microenvironment colon cancer |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.689727/full |
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