Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA.
Department of Environmental and Occupational Health, Departments of Chemistry, Pharmacology and Chemical Biology, Radiation Oncology, University of Pittsburgh, Pennsylvania, USA.
JCI Insight. 2020 Aug 6;5(15):138581. doi: 10.1172/jci.insight.138581.
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.
树突状细胞（DCs）是癌症免疫反应的关键组成部分，主要是因为它们能够交叉呈递肿瘤相关抗原。在癌症中，DC 的交叉呈递受到损害，这可能是癌症免疫疗法成功的障碍之一。在这里，我们报告多形核髓系来源的抑制性细胞（PMN-MDSC）可阻断 DC 的交叉呈递，而不影响这些细胞直接呈递抗原。这种效应不需要直接的细胞接触，并且与脂质转移有关。中性粒细胞（PMN）和PMN-MDSC 同样能够将脂质转移给 DC；然而，PMN 不会影响 DC 的交叉呈递。PMN-MDSC 产生先前被证明参与 DC 交叉呈递受损的氧化截断脂质。PMN-MDSC 中氧化脂质的积累依赖于髓过氧化物酶（MPO）。缺乏 MPO 的 PMN-MDSC 不会影响 DC 的交叉呈递。在 MDSC 耗竭或荷瘤 MPO-KO 小鼠中，体内 DC 对肿瘤相关抗原的交叉呈递得到改善。MPO 的药理学抑制与检查点阻断相结合，可减少不同肿瘤模型中的肿瘤进展。这些数据表明，PMN-MDSC 中 MPO 驱动的脂质过氧化作用可能是 DC 抑制抗原交叉呈递的非细胞自主机制，并提出 MPO 作为增强癌症患者当前免疫疗法疗效的潜在治疗靶点。
