title: Chronic chemoimmunotherapy achieves cure of spontaneous murine mammary tumors via persistent blockade of posttherapy counter-regulation.
abstract: Intratumoral delivery of IL-12 and GM-CSF induces local and systemic antitumor CD8(+) T cell activation and tumor kill. However, the effector response is transient and is rapidly countered by CD4(+) Foxp3(+) T suppressor cell expansion. To determine whether depletion of the pre-existing T suppressor cell pool prior to treatment could diminish posttherapy regulatory cell resurgence, FVBneuN mice bearing advanced spontaneous mammary tumors were treated with cyclophosphamide (CY) 1 d before IL-12/GM-CSF therapy. Administration of CY mediated a significant delay in the post-IL-12/GM-CSF T suppressor cell rebound, resulting in a 7-fold increase in the CD8(+) CTL/T suppressor cell ratio, a 3-fold enhancement of CTL cytotoxicity, and an extension of the effector window from 3 to 7 d. In long-term therapy studies, chronic chemoimmunotherapy promoted a dramatic enhancement of tumor regression, resulting in complete cure in 44% of the mice receiving CY plus IL-12/GM-CSF. Tumor eradication in the chronic therapy setting was associated with the ability to repeatedly rescue and maintain cytotoxic CD8(+) T cell activity. These findings demonstrated that chronic administration of CY in conjunction with immune therapy enhances the initial induction of antitumor T effector cells and, more importantly, sustains their cytotoxic activity over the long-term via persistent blockade of homeostatic counter-regulation.
authors: Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214,USA.
authors: Rachael B
authors: RB
authors: Rowswell-Turner
authors: Jamie L
authors: JL
authors: Harden
authors: Raji E
authors: RE
authors: Nair
authors: Tao
authors: T
authors: Gu
authors: Mehmet O
authors: MO
authors: Kilinc
authors: Nejat K
authors: NK
authors: Egilmez
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004358:Drug Therapy; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000008:administration & dosage*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide