Nie Yan, Huang Hongyan, Guo Mingyan, Chen Jiewen, Wu Wei, Li Wende, Xu Xiaoding, Lin Xiaorong, Fu Wenkui, Yao Yandan, Zheng Fang, Luo Man-Li, Saw Phei Er, Yao Herui, Song Erwei, Hu Hai
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
Breast Tumor Center, SunYat-Sen Memorial Hospital, SunYat-Sen University, Guangzhou, People's Republic of China.
Clin Cancer Res. 2019 Jul 1;25(13):3873-3886. doi: 10.1158/1078-0432.CCR-18-3421. Epub 2019 Mar 19.
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.
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 and . The patient-derived xenografts (PDX) of malignant PTs were used to evaluate the therapeutic effect of CCR5 inhibitor.
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 and . 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.
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.
恶性叶状肿瘤（PT）是一种起源于乳腺导管周围基质细胞的快速进展性肿瘤，目前仍缺乏有效的治疗策略。我们之前的研究表明，肿瘤相关巨噬细胞（TAM）的高密度在PT的恶性进展中起重要作用。TAM分泌大量CCL18，通过与成肌纤维细胞上的受体PIPTNM3结合来促进成肌纤维细胞的分化和侵袭。在此，我们研究PT如何招募和重新极化TAM以驱动恶性进展的机制。
通过细胞因子阵列鉴定PT分泌的细胞因子。用免疫组化评估细胞因子与PT的临床和病理相关性。用原发性PT细胞和巨噬细胞的共培养模型探索细胞因子招募和极化巨噬细胞的机制。使用恶性PT的患者来源异种移植（PDX）评估CCR5抑制剂的治疗效果。
高水平的恶性PT分泌的CCL5与PT的不良预后相关，并且可能是PT的独立预后因素。CCL5与其在巨噬细胞上的受体CCR5结合，从而激活AKT信号传导以招募和重新极化TAM。随后，TAM释放CCL18，通过增强和维持成肌纤维细胞的分化和侵袭来进一步促进恶性PT的侵袭性表型。在人恶性PT的小鼠PDX模型中，经美国食品药品监督管理局（FDA）批准的CCR5抑制剂马拉维若阻断CCL5-CCR5轴，可阻止单核细胞募集到肿瘤并显著抑制肿瘤生长。
我们的研究结果表明，恶性PT通过CCL5-CCR5驱动的信号级联招募和重新极化TAM。因此，在成肌纤维细胞和TAM之间构成了CCL5-CCR5和CCL18-PIPTNM3的正反馈回路，以驱动PT的恶性进展。此外，用马拉维若靶向CCR5代表了一种潜在的临床可用策略来治疗恶性PT。
