Breast Phyllodes Tumors Recruit and Repolarize Tumor-Associated Macrophages via Secreting CCL5 to Promote Malignant Progression, Which Can Be Inhibited by CCR5 Inhibition Therapy
Breast Phyllodes Tumors Recruit and Repolarize Tumor-Associated Macrophages via Secreting CCL5 to Promote Malignant Progression, Which Can Be Inhibited by CCR5 Inhibition Therapy
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乳腺叶状肿瘤通过分泌 CCL5 招募并重新极化肿瘤相关巨噬细胞，促进恶性进展，CCR5 抑制疗法可抑制恶性进展
DOI：
10.1158/1078-0432.ccr-18-3421
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发表时间：
2019-07-01
影响因子：
11.5
通讯作者：
Hu, Hai
中科院分区：
文献类型：
--
作者：
Nie, Yan;Huang, Hongyan;Hu, Hai
目的：恶性叶状肿瘤是一种起源于乳腺导管周围基质细胞的快速进展性肿瘤，目前尚缺乏有效的治疗策略。我们以往的研究表明，高密度的肿瘤相关巨噬细胞()在PTS的恶性进展中起着重要作用。TAMS通过与其受体PIPTNM3结合，分泌大量CCL18，促进肌成纤维细胞的分化和侵袭。在此，我们研究了TAM如何被PTS招募和复极化以驱动恶性进展的机制。实验设计：用细胞因子阵列鉴定PTS分泌的细胞因子。用免疫组织化学方法评估细胞因子与PTS的临床和病理相关性。采用原代PT细胞与巨噬细胞共培养的体内外模型，探讨细胞因子募集和极化巨噬细胞的机制。采用恶性肿瘤患者来源的异种移植物(PDX)评价CCR5抑制剂的治疗效果。结果：恶性甲状旁腺激素分泌的CCL5水平高与PTS预后不良相关，可作为PTS的独立预后因素。巨噬细胞上的CCL5与其受体CCR5结合，激活AKT信号，募集和复极化TAMs。随后，TAMS释放了CCL18，通过增强和维持肌成纤维细胞的分化和侵袭，进一步促进恶性PTS的侵袭性表型。在人类恶性PTS的小鼠PDX模型中，经FDA证实的CCR5抑制剂马拉韦罗阻断了CCL5-CCR5轴，阻止了单核细胞向肿瘤的募集，并显著抑制了肿瘤的生长。结论：我们的研究结果表明，恶性肿瘤通过CCL5-CCR5驱动的信号级联来招募和重新极化TAMs。因此，CCL5-CCR5和CCL18-PIPTNM3在肌成纤维细胞和TAMS之间构成了一个正反馈环，推动了PTS的恶性进展。此外，用马拉韦罗靶向CCR5代表了一种潜在的临床可用的治疗恶性肿瘤的策略。
Purpose: Malignant phyllodes tumor (PT) is a fast-progression neoplasm derived from periductal stromal cells of the breast, which currently still lack effective treatment strategies. Our previous studies showed that the high density of tumor-associated macrophages (TAM) plays an important role in the malignant progression of PTs. TAMs secreted large amount of CCL18 to promote myofibroblast differentiation and invasion via binding to its receptor PIPTNM3 on myofibroblasts. Herein, we investigate the mechanism of how TAMs are recruited and repolarized by PTs to drive the malignant progression. Experimental Design: The cytokines secreted by PTs were identified by the cytokine array. The clinical and pathologic correlations of the cytokine with PTs were estimated with IHC. The mechanisms of the cytokine that recruited and polarized the macrophage were explored with a coculture model of primary PT cells and macrophages in vitro and in vivo. The patient-derived xenografts (PDX) of malignant PTs were used to evaluate the therapeutic effect of CCR5 inhibitor. Results: A high level of malignant PT-secreted CCL5 correlated with poor outcome of PTs and could be an independent prognostic factor of PTs. CCL5 bound to its receptor, CCR5, on macrophages thus activated AKT signaling to recruit and repolarize TAMs. Subsequently, the TAMs released CCL18 to further promote the aggressive phenotype of malignant PTs by enhancing and maintaining the myofibroblast differentiation and invasion in vitro and in vivo. In a murine PDX model of human malignant PTs, the CCL5–CCR5 axis blocked by maraviroc, an FDA-proved CCR5 inhibitor, prevented recruitment of monocytes to the tumor and dramatically suppressed tumor growth. Conclusions: Our findings indicate that malignant PTs recruit and repolarize TAMs through a CCL5-CCR5–driven signaling cascade. Thus, a positive feedback loop of CCL5-CCR5 and CCL18-PIPTNM3 between myofibroblast and TAMs is constituted to drive the malignant progression of PTs. Furthermore, targeting CCR5 with maraviroc represents a potential clinically available strategy to treat malignant PTs.