Myeloid derived suppressor cells promote cross-tolerance in B cell lymphoma by expanding regulatory T cells

By P. Serafini, Stephanie Mgebroff, K. Noonan, I. Borrello. Cancer Research, 2008

688 citations recorded by the source corpus.

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 (MDSCs) as the tolerogenic APCs capable of antigen uptake and presentation to tumor-specific Tregs. MDSC-mediated Treg induction requires arginase but is TGFβ 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 (PDE-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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/73442a6d072da8c376d5c30783a6805cb1915dee

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Citations in the corpus

Myeloid-Derived Suppressor Cells: Linking Inflammation and Cancer (2009, background): “MDSC with the phenotype CD11b Gr-1int (where “int” is “intermediate”) and induced by a mouse fibrosarcoma or colon carcinoma when stimulated with IL-13 through the IL-13R are activated to produce TGF- (59, 76).”
Tumor-induced tolerance and immune suppression depend on the C/EBPbeta transcription factor. (2010, background): “…G-CSF, IL-6, or a combination of these cytokines and monitored the induction of the a chain of the receptor for IL-4 (IL-4Ra, CD124), which was found to be a key component for the activation of the MDSC suppressive Immunity 32, 790–8 program (Gallina et al., 2006; Serafini et al., 2006, 2008).”
T Regulatory Cells: Key Players in Tumor Immune Escape and Angiogenesis (2012, background): “When given at a clinically equivalent dose, gemcitabine resulted in a dramatically reduced number of MDSCs in animal spleens, accompanied by an increase in the antitumor activity of CD8 þ T cells and activated NK cells (64).”
Myeloid-derived-suppressor cells as regulators of the immune system (2009, neutral): “In a different study that evaluated the role of TGFβ (but not the role of IL-4Rα), a TGFβ-specific blocking antibody failed to reverse T-cell anergy in B-cell lymphoma in vitro”
Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function (2010, background): “This receptor is also described as one of the MDSC markers and is responsible for up-regulation of arginase activity [49–51] and increased TGF β production by MDSCs [22,52].”
Tumor-Derived Lactate Modifies Antitumor Immune Response: Effect on Myeloid-Derived Suppressor Cells and NK Cells (2013, background): “It can be speculated that lowered Treg frequencies may have resulted indirectly from improved NK function and/or lowered MDSC levels that have been shown to promote Tregs in animal models (41, 42).”