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Myeloid-Derived Suppressive Cell Expansion Promotes Melanoma Growth and Autoimmunity by Inhibiting CD40/IL27 Regulation in Macrophages
Cancer Research ( IF 12.5 ) Pub Date : 2021-12-01 , DOI: 10.1158/0008-5472.can-21-1148
Julio C Valencia 1 , Rebecca A Erwin-Cohen 1 , Paul E Clavijo 2 , Clint Allen 2 , Michael E Sanford 1 , Chi-Ping Day 3 , Megan M Hess 1 , Morgan Johnson 1 , Jie Yin 1 , John M Fenimore 1 , Ian A Bettencourt 1 , Koichi Tsuneyama 4 , Maria E Romero 5 , Kimberly D Klarmann 1 , Peng Jiang 6 , Heekyong R Bae 1 , Daniel W McVicar 1 , Glenn Merlino 3 , Elijah F Edmondson 7 , Niroshana Anandasabapathy 8 , Howard A Young 1
Affiliation  

The relationship between cancer and autoimmunity is complex. However, the incidence of solid tumors such as melanoma has increased significantly among patients with previous or newly diagnosed systemic autoimmune disease (AID). At the same time, immune checkpoint blockade (ICB) therapy of cancer induces de novo autoinflammation and exacerbates underlying AID, even without evident antitumor responses. Recently, systemic lupus erythematosus (SLE) activity was found to drive myeloid-derived suppressor cell (MDSC) formation in patients, a known barrier to healthy immune surveillance and successful cancer immunotherapy. Cross-talk between MDSCs and macrophages generally drives immune suppressive activity in the tumor microenvironment. However, it remains unclear how peripheral pregenerated MDSC under chronic inflammatory conditions modulates global macrophage immune functions and the impact it could have on existing tumors and underlying lupus nephritis. Here we show that pathogenic expansion of SLE-generated MDSCs by melanoma drives global macrophage polarization and simultaneously impacts the severity of lupus nephritis and tumor progression in SLE-prone mice. Molecular and functional data showed that MDSCs interact with autoimmune macrophages and inhibit cell surface expression of CD40 and the production of IL27. Moreover, low CD40/IL27 signaling in tumors correlated with high tumor-associated macrophage infiltration and ICB therapy resistance both in murine and human melanoma exhibiting active IFNγ signatures. These results suggest that preventing global macrophage reprogramming induced by MDSC-mediated inhibition of CD40/IL27 signaling provides a precision melanoma immunotherapy strategy, supporting an original and advantageous approach to treat solid tumors within established autoimmune landscapes. Significance: Myeloid-derived suppressor cells induce macrophage reprogramming by suppressing CD40/IL27 signaling to drive melanoma progression, simultaneously affecting underlying autoimmune disease and facilitating resistance to immunotherapy within preexisting autoimmune landscapes.

中文翻译:


骨髓源性抑制性细胞扩增通过抑制巨噬细胞中 CD40/IL27 调节促进黑色素瘤生长和自身免疫



癌症与自身免疫之间的关系很复杂。然而,在既往或新诊断的系统性自身免疫性疾病(AID)患者中,黑色素瘤等实体瘤的发病率显着增加。与此同时,即使没有明显的抗肿瘤反应,癌症的免疫检查点阻断 (ICB) 疗法也会诱发自身炎症并加剧潜在的 AID。最近,发现系统性红斑狼疮 (SLE) 活性会促进患者骨髓源性抑制细胞 (MDSC) 的形成,这是健康免疫监测和成功癌症免疫治疗的已知障碍。 MDSC 和巨噬细胞之间的串扰通常会驱动肿瘤微环境中的免疫抑制活性。然而,目前尚不清楚慢性炎症条件下外周预生成的 MDSC 如何调节整体巨噬细胞免疫功能及其对现有肿瘤和潜在狼疮肾炎的影响。在这里,我们发现黑色素瘤引起的 SLE 产生的 MDSC 的致病性扩张驱动了全局巨噬细胞极化,同时影响易患 SLE 的小鼠狼疮性肾炎的严重程度和肿瘤进展。分子和功能数据表明,MDSC 与自身免疫巨噬细胞相互作用,抑制细胞表面 CD40 的表达和 IL27 的产生。此外,在表现出活性 IFNγ 特征的小鼠和人类黑色素瘤中,肿瘤中的低 CD40/IL27 信号传导与高肿瘤相关巨噬细胞浸润和 ICB 治疗耐药性相关。 这些结果表明,防止由 MDSC 介导的 CD40/IL27 信号传导抑制诱导的全局巨噬细胞重编程提供了一种精确的黑色素瘤免疫治疗策略,支持在已建立的自身免疫环境中治疗实体瘤的原始且有利的方法。意义:骨髓源性抑制细胞通过抑制 CD40/IL27 信号传导诱导巨噬细胞重编程,从而驱动黑色素瘤进展,同时影响潜在的自身免疫性疾病,并促进现有自身免疫环境中对免疫治疗的抵抗。
更新日期:2021-12-01
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