Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy

Autor: Dipayan Rudra, George Plitas, Sue Y. Lee, Paula D. Bos, Alexander Y. Rudensky
Rok vydání: 2013
Předmět:
CD4-Positive T-Lymphocytes
Lung Neoplasms
Cell cycle checkpoint
Regulatory T cell
medicine.medical_treatment
Immunology
Mammary Neoplasms
Animal
chemical and pharmacologic phenomena
CD8-Positive T-Lymphocytes
Biology
medicine.disease_cause
T-Lymphocytes
Regulatory
Article
Lymphocyte Depletion
Interferon-gamma
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
Radiation
Ionizing
Tumor Microenvironment
medicine
Animals
Immunology and Allergy
Cell Proliferation
030304 developmental biology
0303 health sciences
Tumor microenvironment
Cell Death
Cell growth
hemic and immune systems
Cell Cycle Checkpoints
Oncogenes
Immunotherapy
Tumor Burden
3. Good health
Killer Cells
Natural
medicine.anatomical_structure
030220 oncology & carcinogenesis
Disease Progression
Cancer research
Female
Carcinogenesis
CD8
Zdroj: The Journal of Experimental Medicine
ISSN: 1540-9538
0022-1007
DOI: 10.1084/jem.20130762
Popis: Transient ablation of regulatory T cells in a murine model of breast carcinogenesis inhibits primary tumor and lung metastatic growth and enhances the therapeutic effect of radiotherapy, but not immune checkpoint blockade.
Rational combinatorial therapeutic strategies have proven beneficial for the management of cancer. Recent success of checkpoint blockade in highly immunogenic tumors has renewed interest in immunotherapy. Regulatory T (T reg) cells densely populate solid tumors, which may promote progression through suppressing anti-tumor immune responses. We investigated the role of T reg cells in murine mammary carcinogenesis using an orthotopic, polyoma middle-T antigen-driven model in Foxp3DTR knockin mice. T reg cell ablation resulted in significant determent of primary and metastatic tumor progression. Importantly, short-term ablation of T reg cells in advanced spontaneous tumors led to extensive apoptotic tumor cell death. This anti-tumor activity was dependent on IFN-γ and CD4+ T cells but not on NK or CD8+ T cells. Combination of T reg cell ablation with CTLA-4 or PD-1/PD-L1 blockade did not affect tumor growth or improve the therapeutic effect attained by T reg cell ablation alone. However, T reg cell targeting jointly with tumor irradiation significantly reduced tumor burden and improved overall survival. Together, our results demonstrate a major tumor-promoting role of T reg cells in an autochthonous model of tumorigenesis, and they reveal the potential therapeutic value of combining transient T reg cell ablation with radiotherapy for the management of poorly immunogenic, aggressive malignancies.
Databáze: OpenAIRE
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