sildenafil-citrate and Lymphoma--B-Cell

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-beta 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.

Topics: Animals; Antigens, Neoplasm; CD11b Antigen; Cell Proliferation; Cells, Cultured; Disease Progression; Genes, T-Cell Receptor; Immune Tolerance; Lymphoma, B-Cell; Mice; Mice, Inbred BALB C; Mice, Transgenic; Myeloid Cells; Phosphodiesterase Inhibitors; Piperazines; Purines; Receptors, Cell Surface; Sildenafil Citrate; Sulfones; T-Lymphocytes, Regulatory; Tumor Escape