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Combination Foretinib and Anti-PD-1 Antibody Immunotherapy for Colorectal Carcinoma
- 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.
- Subjects :
- 0301 basic medicine
Combination therapy
foretinib
Colorectal cancer
QH301-705.5
medicine.medical_treatment
Metastasis
combination therapy
Cell and Developmental Biology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cancer immunotherapy
medicine
tumor microenvironment
Biology (General)
Original Research
Tumor microenvironment
biology
business.industry
Foretinib
Cell Biology
Immunotherapy
medicine.disease
030104 developmental biology
chemistry
colon cancer
030220 oncology & carcinogenesis
biology.protein
Cancer research
anti-PD-1
immunotherapy
Antibody
business
Developmental Biology
Subjects
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