Using macrophage activation to augment immunotherapy of established tumours
| Autor: | Arminder S. Jassar, Jing Sun, Inbal Mishalian, Veena Kapoor, Guanjun Cheng, L-Cs Wang, Liran Levy, Steven M. Albelda, Sunil Singhal, Zvi G. Fridlender |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Lung Neoplasms Myeloid Neutrophils Xanthones tumour-associated macrophages medicine.medical_treatment Cell Antineoplastic Agents CD8-Positive T-Lymphocytes Biology Flow cytometry Carcinoma Lewis Lung Mice 03 medical and health sciences 0302 clinical medicine Immune system Vadimezan Tumor Microenvironment medicine Animals Myeloid Cells 030304 developmental biology Mice Inbred BALB C 0303 health sciences Tumor microenvironment medicine.diagnostic_test Macrophages tumour immunology Immunotherapy Adenocarcinoma Bronchiolo-Alveolar Macrophage Activation Combined Modality Therapy 3. Good health Mice Inbred C57BL lung cancer medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Immunology Female immunotherapy Translational Therapeutics CD8 |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | Background: Successful immunotherapy will require alteration of the tumour microenvironment and/or decreased immune suppression. Tumour-associated macrophages (TAMs) are one major factor affecting tumour microenvironment. We hypothesised that altering TAM phenotype would augment the efficacy of immunotherapy. Methods: We and others have reported that 5,6-Dimethylxanthenone-4-acetic-acid (DMXAA, Vadimezan) has the ability to change TAM phenotypes, inducing a tumour microenvironment conducive to antitumour immune responses. We therefore combined DMXAA with active immunotherapies, and evaluated anti-tumour efficacy, immune cell phenotypes (flow cytometry), and tumour microenvironment (RT–PCR). Results: In several different murine models of immunotherapy for lung cancer, DMXAA-induced macrophage activation significantly augmented the therapeutic effects of immunotherapy. By increasing influx of neutrophils and anti-tumour (M1) macrophages to the tumour, DMXAA altered myeloid cell phenotypes, thus changing the intratumoural M2/non-M2 TAM immunoinhibitory ratio. It also altered the tumour microenvironment to be more pro-inflammatory. Modulating macrophages during immunotherapy resulted in increased numbers, activity, and antigen-specificity of intratumoural CD8+ T cells. Macrophage depletion reduced the effect of combining immunotherapy with macrophage activation, supporting the importance of TAMs in the combined effect. Conclusion: Modulating intratumoural macrophages dramatically augmented the effect of immunotherapy. Our observations suggest that addition of agents that activate TAMs to immunotherapy should be considered in future trials. |
| Databáze: | OpenAIRE |
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