Regorafenib enhances antitumor immunity via inhibition of p38 kinase/Creb1/Klf4 axis in tumor-associated macrophages
| Autor: | Da-Liang Ou, Chiun Hsu, Zi Rui Feng, Chih Hung Chung, Chia Wei Chen, Chia Lang Hsu, Muh Hwa Yang, Bin Shyun Lee, Ann-Lii Cheng |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Carcinoma Hepatocellular Pyridines medicine.medical_treatment T cell Immunology Macrophage polarization Angiogenesis Inhibitors Antineoplastic Agents Mice Transgenic Lymphocyte Activation immunomodulation p38 Mitogen-Activated Protein Kinases chemistry.chemical_compound Kruppel-Like Factor 4 Lymphocytes Tumor-Infiltrating In vivo Regorafenib Cell Line Tumor Tumor-Associated Macrophages medicine Tumor Microenvironment Immunology and Allergy Animals Cyclic AMP Response Element-Binding Protein Protein Kinase Inhibitors RC254-282 MAPK14 Pharmacology Clinical/Translational Cancer Immunotherapy Tumor microenvironment Mice Inbred BALB C Kinase Phenylurea Compounds Liver Neoplasms Neoplasms. Tumors. Oncology. Including cancer and carcinogens Immunotherapy Coculture Techniques Mice Inbred C57BL medicine.anatomical_structure Phenotype Oncology chemistry Cancer research Molecular Medicine immunotherapy Signal Transduction |
| Zdroj: | Journal for Immunotherapy of Cancer Journal for ImmunoTherapy of Cancer, Vol 9, Iss 3 (2021) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundRegorafenib and other multikinase inhibitors may enhance antitumor efficacy of anti-program cell death-1 (anti-PD1) therapy in hepatocellular carcinoma (HCC). Its immunomodulatory effects, besides anti-angiogenesis, were not clearly defined.MethodsIn vivo antitumor efficacy was tested in multiple syngeneic liver cancer models. Murine bone marrow–derived macrophages (BMDMs) were tested in vitro for modulation of polarization by regorafenib and activation of cocultured T cells. Markers of M1/M2 polarization were measured by quantitative reverse transcription PCR (RT-PCR), arginase activity, flow cytometry, and ELISA. Knockdown of p38 kinase and downstream Creb1/Klf4 signaling on macrophage polarization were confirmed by using knockdown of the upstream MAPK14 kinase, chemical p38 kinase inhibitor, and chromatin immunoprecipitation.ResultsRegorafenib (5 mg/kg/day, corresponding to about half of human clinical dosage) inhibited tumor growth and angiogenesis in vivo similarly to DC-101 (anti-VEGFR2 antibody) but produced higher T cell activation and M1 macrophage polarization, increased the ratio of M1/M2 polarized BMDMs and proliferation/activation of cocultured T cells in vitro, indicating angiogenesis-independent immunomodulatory effects. Suppression of p38 kinase phosphorylation and downstream Creb1/Klf4 activity in BMDMs by regorafenib reversed M2 polarization. Regorafenib enhanced antitumor efficacy of adoptively transferred antigen-specific T cells. Synergistic antitumor efficacy between regorafenib and anti-PD1 was associated with multiple immune-related pathways in the tumor microenvironment.ConclusionRegorafenib may enhance antitumor immunity through modulation of macrophage polarization, independent of its anti-angiogenic effects. Optimization of regorafenib dosage for rational design of combination therapy regimen may improve the therapeutic index in the clinic. |
| Databáze: | OpenAIRE |
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