Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells.
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.
Serafini
Paolo
P
Department of Microbiology and Immunology, Dodson Interdisciplinary Immunotherapy Institute, University of Miami, School of Medicine, Miami, Florida 33136, USA. pserafini@med.miami.edu
Mgebroff
Stephanie
S
Noonan
Kimberly
K
Borrello
Ivan
I
D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018450:Disease Progression; D019672:Genes, T-Cell Receptor; D007108:Immune Tolerance / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000502:physiology*; D019139:Tumor Escape / Q000276:immunology*; D053662:Interleukin-4 Receptor alpha Subunit
D000951:Antigens, Neoplasm; D039481:CD11b Antigen; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011956:Receptors, Cell Surface; D000068677:Sildenafil Citrate; D013450:Sulfones; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit