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Polymorphonuclear myeloid-derived suppressor cells limit antigen cross-presentation by dendritic cells in cancer

Alessio Ugolini1, Vladimir A Tyurin2, Yulia Y Tyurina2

  • 1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.

JCI Insight
|June 26, 2020
PubMed

Insights

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) impair cancer immunity by blocking antigen cross-presentation in dendritic cells (DCs). Myeloperoxidase (MPO) drives this inhibition, suggesting MPO as a therapeutic target for cancer immunotherapy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Biochemistry

Background:

  • Dendritic cells (DCs) are crucial for anti-cancer immunity via antigen cross-presentation.
  • Impaired DC cross-presentation is a major hurdle for effective cancer immunotherapy.
  • Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are implicated in immune suppression within the tumor microenvironment.

Purpose of the Study:

  • To investigate the mechanism by which PMN-MDSC inhibit DC cross-presentation.
  • To identify key molecular players involved in PMN-MDSC-mediated suppression.
  • To explore the therapeutic potential of targeting PMN-MDSC in cancer immunotherapy.

Main Methods:

  • Assessing DC antigen cross-presentation in the presence of PMN-MDSC.
  • Investigating lipid transfer between PMN-MDSC and DCs.
  • Utilizing myeloperoxidase (MPO)-deficient models and pharmacological MPO inhibition.
  • Evaluating tumor progression in response to MPO inhibition combined with checkpoint blockade.

Main Results:

  • PMN-MDSC, but not neutrophils (PMN), significantly impaired DC cross-presentation without affecting direct antigen presentation.
  • This inhibition was mediated by lipid transfer from PMN-MDSC to DCs.
  • MPO activity in PMN-MDSC was essential for generating oxidized lipids that block cross-presentation.
  • MPO deficiency or pharmacological inhibition enhanced DC cross-presentation in vivo and improved anti-tumor responses when combined with checkpoint inhibitors.

Conclusions:

  • MPO-driven lipid peroxidation in PMN-MDSC represents a non-cell autonomous mechanism suppressing DC cross-presentation.
  • Targeting MPO in PMN-MDSC offers a promising strategy to overcome immune suppression and enhance cancer immunotherapy efficacy.
Keywords:
Antigen presenting cellsCancer immunotherapyImmunologyOncology

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