MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation.
MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation.
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DOI：
10.1158/2326-6066.cir-15-0070-t
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发表时间：
2016-02
影响因子：
10.1
通讯作者：
Mitchell RA
中科院分区：
文献类型：
--
作者：
Yaddanapudi K;Rendon BE;Lamont G;Kim EJ;Al Rayyan N;Richie J;Albeituni S;Waigel S;Wise A;Mitchell RA
高度侵袭性的癌症“携带”先天和适应性免疫细胞来抑制抗肿瘤淋巴细胞反应。循环髓源性抑制细胞（MDSCs）构成了晚期黑色素瘤患者的大部分单核细胞免疫抑制活性。先前的研究表明，单核细胞源性巨噬细胞迁移抑制因子（MIF）对黑色素瘤小鼠模型中肿瘤相关巨噬细胞（tam）和MDSCs的免疫抑制功能是必需的。在目前的研究中，我们试图确定MIF是否有助于人类黑色素瘤MDSC诱导和t细胞免疫抑制，使用黑色素瘤患者来源的MDSC和人类黑色素瘤诱导的MDSC体外共培养模型。我们现在报道，从晚期黑色素瘤患者中分离的循环MDSCs依赖于MIF来抑制抗原非依赖性t细胞的活化，并且MIF是这些细胞中最大活性氧（ROS）生成所必需的。此外，抑制MIF导致从免疫抑制性MDSC到免疫刺激性树突状细胞（DC）样表型的功能逆转，这至少部分是由于MDSC前列腺素E2 （PGE2）的减少。这些发现表明，单核细胞来源的MIF主要参与人类单核细胞MDSC诱导/免疫抑制功能，MIF的治疗靶向可能为晚期黑色素瘤患者提供一种诱导抗肿瘤DC反应的新方法。
Highly aggressive cancers “entrain” innate and adaptive immune cells to suppress anti-tumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSCs) constitute the bulk of monocytic immunosuppressive activity in late stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immune suppressive function of tumor-associated macrophages (TAMs) and MDSCs in mouse models of melanoma. In the current study we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo co-culture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species (ROS) generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immune suppressive MDSC to an immunostimulatory dendritic cell (DC)-like phenotype that is at least partly due to reductions in MDSC prostaglandin E2 (PGE2). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immune suppressive function and that therapeutic targeting of MIF may provide a novel means of inducing anti-tumor DC responses in late stage melanoma patients.