Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer

Aldinucci, Donatella; Casagrande, Naike

doi:10.3390/ijms19051477

Cited by 109 publications

(94 citation statements)

References 110 publications

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“…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 ).…”

Section: Discussionsupporting

confidence: 52%

CCR5 status and metastatic progression in colorectal cancer

et al. 2019

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Multiple reports have highlighted the importance of the local immunological cellular composition (i.e. the density of effector T cells and macrophage polarization state) in predicting clinical outcome in advanced metastatic stage of colorectal cancer. However, in spite of the general association between a high effector T cell density and improved outcome, our recent work has revealed a specific lymphocyte-driven cancer cell-supporting signal. Indeed, lymphocyte-derived CCL5 supports CCR5-positive tumor cell proliferation and thereby fosters tumor growth in metastatic liver lesions. Upon systematic analysis of CCR5 expression by tumor cells using immunohistochemistry, we observed that the intensity of CCR5 increases with primary tumor size and peaks in T4 tumors. In liver metastases however, though CCR5 expression intensity is globally heightened compared to primary tumors, alterations in the expression patterns appear, leading to "patchiness" of the stain. CCR5 patchiness is, therefore, a signature of liver metastases in our cohort (n = 97 specimens) and relates to globally decreased expression intensity, but does not influence the extent of the response to CCR5 inhibitor Maraviroc in patients. Moreover, CCR5 patchiness relates to a poor immune landscape characterized by a low cytotoxic-to-regulatory T cell ratio at the invasive margin and enriched cellular and molecular markers of macrophage M2 polarization. Finally, because higher numbers of PD-1-and CTLA-4-positive cells surround tumors with patchy CCR5 expression, one can speculate that these tumors potentially respond to immune checkpoint blockade. This hypothesis is corroborated by the prolonged disease-free survival and disease-specific survival observed in patients with low gene expression of CCR5 in metastases from two publically available cohorts. These observations highlight the complex role of the CCL5-CCR5 axis in CRC metastatic progression and warrant further investigations.

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Section: Discussionsupporting

confidence: 52%

CCR5 status and metastatic progression in colorectal cancer

et al. 2019

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“…CCR5 is predominantly expressed on T cells, macrophages, dendritic cells, eosinophils, and microglia (18). Several CCR5 receptor antagonists are used as antiretroviral drug in treatment of HIV infection (51). Given that CCR5 is expressed on the TAMs and blocking the CCL5-CCR5 axis can prevent the TAM polarization, several studies have applied CCR5 inhibitors for cancer treatment in animal models, such as breast and liver cancers (33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

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

Nie

Huang

Guo

et al. 2019

Clinical Cancer Research

115

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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.

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“…Since the CCR5/CCL5 interaction is involved in the motility, migration, and invasion of various cancer cells [18,24,25], we analyzed the functional significance of this interaction in the migration of HCC cells. Three-dimensional cultures of SNU387, PLC/PFR-5, and SK-HEP-1 cells exposed to CCL5 were used (Figure 7).…”

Section: The Ccr5/ Ccl5 Interaction Induces Metastatic Behavior In Hcmentioning

confidence: 99%

Biological and Clinical Significance of the CCR5/CCL5 Axis in Hepatocellular Carcinoma

Singh

Mishra

Rivers

et al. 2020

Cancers

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Despite the improvement in survival for patients with liver cancer (LCa) in recent decades, only one in five patients survive for 5 years after diagnosis. Thus, there is an urgent need to find new treatment options to improve patient survival. For various cancers, including LCa, the chemokine CCL5 (RANTES) facilitates tumor progression and metastasis. Since the function of the CCR5/CCL5 interaction in LCa cell proliferation and migration is poorly understood, the present study was undertaken to investigate the role of the CCR5/CCL5 axis in these processes. Flow cytometry, RT-PCR, Western blot, and immunofluorescence techniques were used to quantify the expression of CCR5 and CCL5 in LCa cells. To determine the biological significance of CCR5 expressed by LCa cell lines, a tissue microarray of LCas stained for CCR5 and CCL5 was analyzed. The results showed higher expression (p < 0.001) of CCR5 and CCL5 in hepatocellular carcinoma (HCC) tissues compared to non-neoplastic liver tissues. Furthermore, to delineate the role of the CCR5/CCL5 interaction in LCa cell proliferation and migration, various LCa cells were treated with maraviroc, a CCR5 antagonist, in the presence of CCL5. These data demonstrated the biological and clinical significance of the CCR5/CCL5 axis in LCa progression. The targeting of this axis is a promising avenue for the treatment of LCa.

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Inhibition of the CCL5/CCR5 Axis against the Progression of Gastric Cancer

Cited by 109 publications

References 110 publications

CCR5 status and metastatic progression in colorectal cancer

CCR5 status and metastatic progression in colorectal cancer

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

Biological and Clinical Significance of the CCR5/CCL5 Axis in Hepatocellular Carcinoma

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