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

Authors :
Yanfang Yang
Chengli Yang
Mengdan Wu
Yuxi Wang
Shengyan Zhao
Lishi Zeng
Xiaohua Jiang
Yin Lu
Qinhuai Lai
Cheng Huang
Yangping Wu
Jinliang Yang
Lantu Gou
Ting Kong
Jun Mou
Yuqin Yao
Yujia Peng
Yuyan Li
Yuyin Fu
Source :
Frontiers in Cell and Developmental Biology, Vol 9 (2021), Frontiers in Cell and Developmental Biology
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

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.

Details

Language :
English
Volume :
9
Database :
OpenAIRE
Journal :
Frontiers in Cell and Developmental Biology
Accession number :
edsair.doi.dedup.....1550d60ca258e5ec5d48ff1bb826bb59
Full Text :
https://doi.org/10.3389/fcell.2021.689727/full