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

Yulia Y. Tyurina,Alessio Ugolini,Valerian E. Kagan,Evgenii N. Tcyganov,Filippo Veglia,Vladimir A. Tyurin,Laxminarasimha Donthireddy,Dmitry I. Gabrilovich

doi:10.1172/jci.insight.138581

Abstract

DCs are a 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 patients with cancer.

Highlights

DCs are highly specialized antigen-presenting cells (APC) [1, 2]. They can be broadly divided into 3 subsets: classical DCs, plasmacytoid DCs, and inflammatory DCs. cDCs consist of 2 large groups: cDC type 1 and type 2. cDC1 are key players in the regulation of cancer immune responses due to their ability to cross-present antigens to CD8+ T cells and to generate cytotoxic effector T cell responses [3,4,5,6]
PMN-Myeloid-derived suppressor cells (MDSC) dramatically reduced the ability of cDC1 to present OVA-derived antigens to peptide-specific OT-1 CD8+ T cells (Figure 1B) without impairing the direct presentation of short peptide (Figure 1C)
Our study suggests a mechanism of negative regulation of cross-presentation by DCs in cancer, involving possible transfer of oxidized lipids from PMN-MDSC to cDC1

Summary

Introduction

DCs are highly specialized antigen-presenting cells (APC) [1, 2]. They can be broadly divided into 3 subsets: classical DCs (cDC), plasmacytoid DCs, and inflammatory DCs. cDCs consist of 2 large groups: cDC type 1 (cDC1) and type 2 (cDC2). cDC1 are key players in the regulation of cancer immune responses due to their ability to cross-present antigens to CD8+ T cells and to generate cytotoxic effector T cell responses [3,4,5,6]. DCs are highly specialized antigen-presenting cells (APC) [1, 2] They can be broadly divided into 3 subsets: classical DCs (cDC), plasmacytoid DCs, and inflammatory DCs. cDCs consist of 2 large groups: cDC type 1 (cDC1) and type 2 (cDC2). CDC1 are key players in the regulation of cancer immune responses due to their ability to cross-present antigens to CD8+ T cells and to generate cytotoxic effector T cell responses [3,4,5,6]. Their presence is critically important for the success of immunotherapies, such as adoptive T cell transfer and checkpoint blockade [7,8,9]. The source of oxidized lipids in DCs remained unclear, because the machinery for lipid oxidation is largely missing in cDC1

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Conclusion