1. Academic Validation
  2. Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma

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

  • Front Cell Dev Biol. 2021 Jul 8;9:689727. doi: 10.3389/fcell.2021.689727.
Yuyin Fu 1 Yujia Peng 1 Shengyan Zhao 1 Jun Mou 2 Lishi Zeng 1 Xiaohua Jiang 1 Chengli Yang 1 Cheng Huang 1 Yuyan Li 1 Yin Lu 1 Mengdan Wu 1 Yanfang Yang 1 Ting Kong 1 Qinhuai Lai 1 Yangping Wu 3 Yuqin Yao 4 Yuxi Wang 5 Lantu Gou 1 Jinliang Yang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
  • 2 Laboratory of Infectious Diseases and Vaccine, West China Hospital, Sichuan University, Chengdu, China.
  • 3 Department of Clinical Research Management, West China Hospital, Sichuan University, Chengdu, China.
  • 4 West China School of Public Health and Healthy Food Evaluation Research Center/No. 4 West China Teaching Hospital, Sichuan University, Chengdu, China.
  • 5 Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China.
Abstract

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.

Keywords

anti-PD-1; colon cancer; combination therapy; foretinib; immunotherapy; tumor microenvironment.

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