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

Paolo Serafini, Stephanie Mgebroff, Kimberly Noonan, Ivan Borrello

Research output: Contribution to journalArticle

428 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5439-5449
Number of pages11
JournalCancer Research
Volume68
Issue number13
DOIs
StatePublished - Jul 1 2008

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B-Cell Lymphoma
Regulatory T-Lymphocytes
Antigens
Neoplasms
Type 5 Cyclic Nucleotide Phosphodiesterases
T-Lymphocytes
Arginase
Antigen Presentation
Transforming Growth Factors
Neoplasm Antigens
Antigen-Presenting Cells
Immunosuppressive Agents
Myeloid-Derived Suppressor Cells
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. / Serafini, Paolo; Mgebroff, Stephanie; Noonan, Kimberly; Borrello, Ivan.

In: Cancer Research, Vol. 68, No. 13, 01.07.2008, p. 5439-5449.

Research output: Contribution to journalArticle

Serafini, Paolo ; Mgebroff, Stephanie ; Noonan, Kimberly ; Borrello, Ivan. / Myeloid-derived suppressor cells promote cross-tolerance in B-cell lymphoma by expanding regulatory T cells. In: Cancer Research. 2008 ; Vol. 68, No. 13. pp. 5439-5449.
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