Abstract
Triple-negative breast cancer (TNBC) accounts for approximately 10–15% of all breast cancer cases and is characterized by high invasiveness, high metastatic potential, relapse proneness, and poor prognosis. M2-like tumor-associated macrophages (TAMs) contribute to tumorigenesis and are promising targets for inhibiting breast cancer metastasis. Therefore, we investigated whether melittin-conjugated pro-apoptotic peptide (TAMpepK) exerts therapeutic effects on breast cancer metastasis by targeting M2-like TAMs. TAMpepK is composed of M2-like TAM binding peptide (TAMpep) and pro-apoptotic peptide d(KLAKLAK)2 (dKLA). A metastatic mouse model was constructed by injecting 4T1-luc2 cells either orthotopically or via tail vein injection, and tumor burden was quantified using a bioluminescence in vivo imaging system. We found that TAMpepK suppressed lung and lymph node metastases of breast cancer by eliminating M2-like TAMs without affecting the viability of M1-like macrophages and resident macrophages in the orthotopic model. Furthermore, TAMpepK reduced pulmonary seeding and the colonization of tumor cells in the tail vein injection model. The number of CD8+ T cells in contact with TAMs was significantly decreased in tumor nodules treated with TAMpepK, resulting in the functional activation of cytotoxic CD8+ T cells. Taken together, our findings suggest that TAMpepK could be a novel therapeutic agent for the inhibition of breast cancer metastasis by targeting M2-like TAMs.
Highlights
Triple-negative breast cancer (TNBC), which accounts for approximately 10–15% of all breast cancers, refers to a specific subtype that tests negative for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2)
The hybrid peptide TAMpepK developed in our previous study [22] showed a strong antitumor effect in lung-cancer-bearing mice, which was found to be mediated by the specific mitochondrial death of M2-like tumor-associated macrophages (TAMs)
To further confirm whether the anti-metastatic effect of TAMpepK is related to the infiltration of cytotoxic CD8+ T cells into tumor colonies, we investigated the correlation between TAMs and CD8+ T cells in pulmonary nodules in tail vein injection cancer-challenged mouse lungs using immunofluorescence staining (Figure 5A)
Summary
Triple-negative breast cancer (TNBC), which accounts for approximately 10–15% of all breast cancers, refers to a specific subtype that tests negative for estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2)protein [1]. The clinical features of TNBC include high invasiveness, high metastatic potential, proneness to relapse, and poor prognosis [2]. The mortality rate of TNBC patients within 3 months of recurrence is as high as 75% [3,4]. Owing to its special molecular phenotype, TNBC is not sensitive to endocrine therapy or molecular-targeted therapy. Chemotherapy is the main systemic treatment, but the efficacy of conventional postoperative adjuvant chemoradiotherapy is poor [5]. Recent studies have reported that the tumor microenvironment, composed of cancer-associated fibroblasts and immune cells, plays an important role in the development and treatment resistance of TNBC [6]. There is an urgent need to develop novel treatment regimens and targets
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