Ccl3 enhances docetaxel chemosensitivity in breast cancer by triggering proinflammatory macrophage polarization

Abstract

BackgroundAlthough the antitumor efficacy of docetaxel (DTX) has long been attributed to the antimitotic activities, its impact on the tumor microenvironment (TME) has recently gained more attention. Macrophages are a major component of the TME and play a critical role in DTX efficacy; however, the underlying action mechanisms remain unclear.MethodsDTX chemotherapeutic efficacy was demonstrated via both macrophage depletion and C–C motif chemokine ligand 3 (Ccl3)-knockout transgenic allograft mouse model. Ccl3-knockdown and Ccl3-overexpressing breast cancer cell allografts were used for the in vivo study. Combination therapy was used to evaluate the effect of Ccl3 induction on DTX chemosensitivity. Vital regulatory molecules and pathways were identified using RNA sequencing. Macrophage phagocytosis of cancer cells and its influence on cancer cell proliferation under DTX treatment were assessed using an in vitro coculture assay. Serum and tumor samples from patients with breast cancer were used to demonstrate the clinical relevance of our study.ResultsOur study revealed that Ccl3 induced by DTX in macrophages and cancer cells was indispensable for the chemotherapeutic efficacy of DTX. DTX-induced Ccl3 promoted proinflammatory macrophage polarization and subsequently facilitated phagocytosis of breast cancer cells and cancer stem cells. Ccl3 overexpression in cancer cells promoted proinflammatory macrophage polarization to suppress tumor progression and increase DTX chemosensitivity. Mechanistically, DTX induced Ccl3 by relieving the inhibition of cAMP-response element binding protein on Ccl3 via reactive oxygen species accumulation, and Ccl3 then promoted proinflammatory macrophage polarization via activation of the Ccl3–C-C motif chemokine receptor 5–p38/interferon regulatory factor 5 pathway. High CCL3 expression predicted better prognosis, and high CCL3 induction revealed better DTX chemosensitivity in patients with breast cancer. Furthermore, both the Creb inhibitor and recombinant mouse Ccl3 significantly enhanced DTX chemosensitivity.ConclusionsOur results indicate that Ccl3 induced by DTX triggers proinflammatory macrophage polarization and subsequently facilitates phagocytosis of cancer cells. Ccl3 induction in combination with DTX may provide a promising therapeutic rationale for increasing DTX chemosensitivity in breast cancer.

Targeting Breast Cancer Stem Cells

“…CCL20 not only facilitates the expansion of BCSCs but also enhances drug resistance in TNBC 153 . C-C Motif Chemokine Ligand 3 (CCL3) from cancer cells and macrophages enhances the phagocytic ability of docetaxel-induced M1 macrophages to BCSCs 154 . Blocking the C-X-C motif chemokine ligand-1 (CXCL1) produced by BCSCs impedes BCSC proliferation and mammosphere formation 155 .…”

PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway

“… 57 , 58 Our recent reports showed that DTX induced C-C motif chemokine ligand 3 (CCL3) secretion in macrophages and triggered proinflammatory polarization of macrophages to inhibit breast cancer progression. 59 However, most patients eventually become chemo-resistant accompanied with tumor progression. There is considerable evidence that CSC enrichment played a key role in contributing to chemotherapy resistance of DTX.…”

Multi-omics analysis revealing a senescence-relevant lncRNAs signature for the assessment of response to immunotherapy for breast cancer

“…Sheng et al found that docetaxel-induced Ccl3 could promote the proinflammatory macrophage polarization and subsequently accelerate phagocytosis of tumor cells. [45] In recent years, lncRNA-based prognostic signature for BRCA have been emerging. Lv et al developed an m6A-related lncRNA signature as predictive biomarkers for BRCA.…”