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Myeloid-Derived Suppressor Cells Promote Cross-Tolerance in B-Cell Lymphoma by Expanding Regulatory T Cells

¹ Department of Microbiology and Immunology, Dodson Interdisciplinary Immunotherapy Institute, University of Miami, School of Medicine, Miami, Florida, and ² Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland

Requests for reprints: Ivan Borrello, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB-1 Room 453, Baltimore, MD 21231. Phone: 410-955-4967; Fax: 410-614-9705; E-mail: borreiv{at}jhmi.edu or Paolo Serafini, Dodson Interdisciplinary Immunotherapy Institute, University of Miami, 1550 NW 10 Avenue, (M710) PAP Building, Room 234, Miami, FL 33136. Phone: 305-243-7917; Fax: 305-243-4409; E-mail: pserafini{at}med.miami.edu.

Key Words: myeloid-derived suppressor cells • regulatory T cells • tumor-induced tolerance • lymphoma • sildenafil

Tumor-induced T-cell tolerance is a major mechanism that facilitates tumor progression and limits the efficacy of immune therapeutic interventions. Regulatory T cells (Treg) play a central role in the induction of tolerance to tumor antigens, yet the precise mechanisms regulating its induction in vivo remain to be elucidated. Using the A20 B-cell lymphoma model, here we identify myeloid-derived suppressor cells (MDSC) as the tolerogenic antigen presenting cells capable of antigen uptake and presentation to tumor-specific Tregs. MDSC-mediated Treg induction requires arginase but is transforming growth factor-β independent. In vitro and in vivo inhibition of MDSC function, respectively, with NOHA or sildenafil abrogates Treg proliferation and tumor-induced tolerance in antigen-specific T cells. These findings establish a role for MDSCs in antigen-specific tolerance induction through preferential antigen uptake mediating the recruitment and expansion of Tregs. Furthermore, therapeutic interventions, such as in vivo phosphodiesterase 5–inhibition, which effectively abrogate the immunosuppressive role of MDSCs and reduce Treg numbers, may play a critical role in delaying and/or reversing tolerance induction. [Cancer Res 2008;68(13):5439–49]