title: Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy.
abstract: 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 Foxp3(DTR) 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.
authors.affiliation: Memorial Sloan-Kettering Cancer Center; and Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Paula D
authors.initials: PD
authors.lastname: Bos
authors.forename: George
authors.initials: G
authors.lastname: Plitas
authors.forename: Dipayan
authors.initials: D
authors.lastname: Rudra
authors.forename: Sue Y
authors.initials: SY
authors.lastname: Lee
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Rudensky
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000528:radiation effects; D059447:Cell Cycle Checkpoints / Q000528:radiation effects; D016923:Cell Death / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D018450:Disease Progression; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000528:radiation effects; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D008212:Lymphocyte Depletion; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D009857:Oncogenes / Q000235:genetics*; D011839:Radiation, Ionizing; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000528:radiation effects; D047368:Tumor Burden / Q000276:immunology / Q000528:radiation effects; D059016:Tumor Microenvironment / Q000528:radiation effects
chemical_list: D007371:Interferon-gamma