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Lenvatinib plus anti-PD-1 antibody combination treatment activates CD8+ T cells through reduction of tumor-associated macrophage and activation of the interferon pathway
- Source :
- PLoS ONE, PLoS ONE, Vol 14, Iss 2, p e0212513 (2019)
- Publication Year :
- 2019
- Publisher :
- Public Library of Science (PLoS), 2019.
-
Abstract
- Lenvatinib is a multiple receptor tyrosine kinase inhibitor targeting mainly vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptors. We investigated the immunomodulatory activities of lenvatinib in the tumor microenvironment and its mechanisms of enhanced antitumor activity when combined with a programmed cell death-1 (PD-1) blockade. Antitumor activity was examined in immunodeficient and immunocompetent mouse tumor models. Single-cell analysis, flow cytometric analysis, and immunohistochemistry were used to analyze immune cell populations and their activation. Gene co-expression network analysis and pathway analysis using RNA sequencing data were used to identify lenvatinib-driven combined activity with anti-PD-1 antibody (anti-PD-1). Lenvatinib showed potent antitumor activity in the immunocompetent tumor microenvironment compared with the immunodeficient tumor microenvironment. Antitumor activity of lenvatinib plus anti-PD-1 was greater than that of either single treatment. Flow cytometric analysis revealed that lenvatinib reduced tumor-associated macrophages (TAMs) and increased the percentage of activated CD8+ T cells secreting interferon (IFN)-γ+ and granzyme B (GzmB). Combination treatment further increased the percentage of T cells, especially CD8+ T cells, among CD45+ cells and increased IFN-γ+ and GzmB+ CD8+ T cells. Transcriptome analyses of tumors resected from treated mice showed that genes specifically regulated by the combination were significantly enriched for type-I IFN signaling. Pretreatment with lenvatinib followed by anti-PD-1 treatment induced significant antitumor activity compared with anti-PD-1 treatment alone. Our findings show that lenvatinib modulates cancer immunity in the tumor microenvironment by reducing TAMs and, when combined with PD-1 blockade, shows enhanced antitumor activity via the IFN signaling pathway. These findings provide a scientific rationale for combination therapy of lenvatinib with PD-1 blockade to improve cancer immunotherapy.
- Subjects :
- 0301 basic medicine
Programmed Cell Death 1 Receptor
Cancer Treatment
Melanoma, Experimental
Gene Expression
CD8-Positive T-Lymphocytes
Lymphocyte Activation
White Blood Cells
Mice
chemistry.chemical_compound
Spectrum Analysis Techniques
0302 clinical medicine
Animal Cells
Interferon
Medicine and Health Sciences
Tumor Microenvironment
Cytotoxic T cell
Mice, Inbred BALB C
Multidisciplinary
T Cells
Antibodies, Monoclonal
Animal Models
Flow Cytometry
Oncology
Experimental Organism Systems
Spectrophotometry
030220 oncology & carcinogenesis
Quinolines
Medicine
Cytophotometry
Cellular Types
Lenvatinib
Research Article
Signal Transduction
medicine.drug
Science
Immune Cells
Immunology
Mice, Nude
Cytotoxic T cells
Mouse Models
Antineoplastic Agents
Tumor-associated macrophage
Research and Analysis Methods
GZMB
03 medical and health sciences
Model Organisms
Cell Line, Tumor
Genetics
medicine
Animals
Immunologic Factors
Immunohistochemistry Techniques
Protein Kinase Inhibitors
Tumor microenvironment
Blood Cells
Macrophages
Phenylurea Compounds
Biology and Life Sciences
Cell Biology
Neoplasms, Experimental
Histochemistry and Cytochemistry Techniques
Mice, Inbred C57BL
Granzyme B
030104 developmental biology
chemistry
Animal Studies
Immunologic Techniques
Cancer research
Interferons
CD8
Subjects
Details
- ISSN :
- 19326203
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- PLOS ONE
- Accession number :
- edsair.doi.dedup.....68ed8542333bdfe89278c3e714ba7cd1