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

Yuyin Fu,Jun Mou,Yangping Wu,Lishi Zeng,Chengli Yang,Yuxi Wang,Yin Lu,Mengdan Wu,Xiaohua Jiang,Cheng Huang,Yujia Peng,Lantu Gou,Yuqin Yao,Yanfang Yang,Jinliang Yang,Qinhuai Lai,Ting Kong,Shengyan Zhao,Yuyan Li

doi:10.3389/fcell.2021.689727

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.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide
These results demonstrated that the levels of PD-L1, JAK2, STAT1, phospho-STAT1(S727), phospho-STAT1(Y701) were elevated following Foretinib treatment (Figures 1A,B)
These results demonstrated that Foretinib could regulate the immune cells associated with colon cancer in vivo

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Immune checkpoint inhibitors (ICIs) that target PDCD1/CD274(PD-1/PD-L1) have been used to treat a variety of malignant tumors, including melanoma, lung cancer, renal cell cancer, head and neck cancer, Hodgkin’s disease, urothelial cancer (Ribas and Wolchok, 2018; Xiao et al, 2020) and CRC with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H). CRC with dMMR/MSH-H only accounts for approximately 15% of all advanced CRC cases, the majority of patients cannot benefit ICIs (Overman et al, 2017; Oliveira et al, 2019). The poor therapeutic effect for CRC patients is associated with the immunosuppressive tumor microenvironment (TME), which causes resistance to immune checkpoint blockade (ICB) (Pitt et al, 2016). There is an urgent need to overcome the CRC associated immunosuppression, which would enable the proportion of patients who benefit from PD-1/PD-L1 blockade to be expanded. Numerous preclinical studies have indicated that the combination of ICIs with other treatments such as chemotherapy, radiation therapy and targeted therapy could be a promising approach to overcome immunosuppression and improve therapeutic efficacy (O’Neill and Cao, 2019)

Methods

Results

Discussion

Conclusion