Breast Phyllodes Tumors Recruit and Repolarize Tumor-Associated Macrophages via Secreting CCL5 to Promote Malignant Progression, Which Can Be Inhibited by CCR5 Inhibition Therapy

Abstract

Purpose: Malignant phyllodes tumor (PT) is a fastprogression 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.

CCR5 status and metastatic progression in colorectal cancer

“…In the phase I clinical trial testing Maraviroc as a monotherapy in advanced colorectal cancer, this translated into selective necrosis of tumor cells in liver metastases. 15 This association between CCR5 expression at the surface of macrophages, and the activation of a M2 polarization program upon its activation is supported by other reports 55 and most compellingly, the functional (re-)activation of a M1 program in TAMs using Maraviroc has been shown as well by others in other tumor entities, such as non-Hodgkin lymphoma, 56 breast cancer 55 or gastric cancer (reviewed in 57 ).…”

CCL5 derived from tumor-associated macrophages promotes prostate cancer stem cells and metastasis via activating β-catenin/STAT3 signaling

“…For example, it has been reported that TAMs could promote prostate cancer migration through activation of the CCL22-CCR4 axis 32 . TAMs released CCL18 to further promote the aggressive phenotype of breast phyllodes tumors by enhancing and maintaining the myofibroblast differentiation and invasion in vitro and in vivo 23 . Our previous study indicated that CCL5 was one of the most abundant chemokines secreted by TAMs 22 .…”

“…Our previous study indicated that CCL5, another member of the CC chemokine family, was a more abundant TAMs-secreted chemokine than CCL2 22 . Additionally, it has been reported that the CCL5-CCR5 axis blockage in the TME may represent a potential clinically available strategy for inhibiting human breast phyllodes tumor growth 23 . Nevertheless, the prognostic value of TAMs-secreted CCL5 for prostate cancer as well as its modulatory effect on both prostate cancer cells and PCSCs cells remain unclear and deserve further investigations.…”

CD163+ tumor‐associated macrophage accumulation in breast cancer patients reflects both local differentiation signals and systemic skewing of monocytes

“…In addition, cancer‐associated fibroblasts producing CXCL12 stimulate the migration of TAMs towards tumor‐associated vessels that may promote the extravasation of tumor cells to the bloodstream . In phyllode malignant breast tumors, a particular BC subtype, CCL5 produced by tumor cells promotes the polarisation of TAMs into IL18 + producers, via the AKT pathway leading to a positive feedback for tumor promotion and aggressiveness . Moreover under hypoxia, murine melanoma tumors secrete exosomes able to up‐regulate oxidative phosphorylation in bone marrow‐derived macrophages, inducing their polarisation towards F4/80 + CD206 high M2‐MΦ, favoring tumor development …”

“…58 In phyllode malignant breast tumors, a particular BC subtype, CCL5 produced by tumor cells promotes the polarisation of TAMs into IL18 + producers, via the AKT pathway leading to a positive feedback for tumor promotion and aggressiveness. 60 Moreover under hypoxia, murine melanoma tumors secrete exosomes able to up-regulate oxidative phosphorylation in bone marrow-derived macrophages, inducing their polarisation towards F4/80 + CD206 high M2-MΦ, favoring tumor development. 61 Outstandingly, our data suggest that tumorderived factors affect monocytes in the bloodstream of patient.…”