Dendritic cells (DCs) are critical component of immune responses in cancer primarily due to their ability to cross-present tumor associated antigens. Cross-presentation by DCs in cancer is impaired, which may represent one of the obstacles for the success of cancer immunotherapies. Here, we report that polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) blocked cross-presentation by DCs without affecting direct presentation of antigens by these cells. This effect did not require direct cell-cell contact and was associated with transfer of lipids. Neutrophils (PMN) and PMN-MDSC transferred lipid to DCs equally well, however PMN did not affect DC cross-presentation. PMN-MDSC generate oxidatively truncated lipids previously shown to be involved in impaired cross-presentation by DCs. Accumulation of oxidized lipids in PMN-MDSC was dependent on myeloperoxidase (MPO). MPO deficient PMN-MDSC did not affect cross-presentation by DCs. Cross-presentation of tumor associated antigens in vivo by DCs was improved in MDSC depleted or tumor-bearing MPO KO mice. Pharmacological inhibition of MPO in combination with checkpoint blockade reduced tumor progression in different tumor models. These data suggest MPO-driven lipid peroxidation in PMN-MDSC as a possible non-cell autonomous mechanism of inhibition of antigen cross-presentation by DCs and propose MPO as potential therapeutic target to enhance the efficacy of current immunotherapies for cancer patients.
Alessio Ugolini, Vladimir Tyurin, Yulia Tyurina, Evgenii Tsyganov, Laxminarasimha Donthireddy, Valerian E Kagan, Dmitry I. Gabrilovich, Filippo Veglia
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