Myeloid-derived suppressor cells adhere to physiologic STAT3-vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape

Peter A. Cohen, Jennifer S. Ko, Walter J. Storkus, Christopher D. Spencer, Judy M. Bradley, Jessica E. Gorman, Dustin B. McCurry, Soroya Zorro-Manrique, Anna Lucia Dominguez, Latha B. Pathangey, Patricia A. Rayman, Brian I. Rini, Sandra J. Gendler, James H. Finke

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

The receptor tyrosine kinase inhibitor, sunitinib, is astonishingly effective in its capacity to reduce MDSCs in peripheral tissues such as blood (human) and spleen (mouse), restoring responsiveness of bystander T lymphocytes to TcR stimulation. Sunitinib blocks proliferation of undifferentiated MDSCs and decreases survival of more differentiated neutrophilic MDSC (n-MDSC) progeny. Ironically, sunitinib's profound effects are observed even in a total absence of detectable anti-tumor therapeutic response. This is best explained by the presence of disparate MDSC-conditioning stimuli within individual body compartments, allowing sensitivity and resistance to sunitinib to coexist within the same mouse or patient. The presence or absence of GM-CSF is likely the major determinant in each compartment, given that GM-CSF's capacity to preempt STAT3-dependent with dominant STAT5-dependent hematopoietic programming confers sunitinib resistance and redirects differentiation from the n-MDSC lineage to the more versatile monocytoid (m-MDSC) lineage. The clinical sunitinib experience underscores that strategies for MDSC and Treg depletions must be mindful of disparities among body compartments to avoid sanctuary effects. Ironically, m-MDSCs manifesting resistance to sunitinib also have the greatest potential to differentiate into tumoricidal accessory cells, by virtue of their capacity to respond to T cell-secreted IFN-γ or to TLR agonists with nitric oxide and peroxynitrate production.

Original languageEnglish (US)
Pages (from-to)680-710
Number of pages31
JournalImmunological Investigations
Volume41
Issue number6-7
DOIs
StatePublished - Aug 2012

Keywords

  • G-CSF
  • GM-CSF
  • MDSC
  • Myeloid-derived suppressor cells
  • STAT3
  • STAT5
  • Sunitinib

ASJC Scopus subject areas

  • Immunology

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