Department of Physiology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, Korea.
Cancer Immunology Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea.
Int J Mol Sci. 2022 Feb 15;23(4):2157. doi: 10.3390/ijms23042157.
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) (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.
三阴性乳腺癌（TNBC）约占所有乳腺癌病例的 10-15%，其特征为高侵袭性、高转移潜能、易复发和预后不良。M2 样肿瘤相关巨噬细胞（TAMs）有助于肿瘤发生，是抑制乳腺癌转移的有前途的靶点。因此，我们研究了蜂毒素缀合的促凋亡肽（TAMpepK）是否通过靶向 M2 样 TAMs 对乳腺癌转移发挥治疗作用。TAMpepK 由 M2 样 TAM 结合肽（TAMpep）和促凋亡肽 d（KLAKLAK）（dKLA）组成。通过原位或尾静脉注射 4T1-luc2 细胞构建转移性小鼠模型，并使用活体生物发光成像系统定量肿瘤负荷。我们发现 TAMpepK 通过消除 M2 样 TAMs 抑制乳腺癌的肺和淋巴结转移，而不影响原位模型中 M1 样巨噬细胞和固有巨噬细胞的活力。此外，TAMpepK 减少了尾静脉注射模型中肺部播种和肿瘤细胞的定植。与 TAMs 接触的 CD8 T 细胞数量在 TAMpepK 处理的肿瘤结节中显著减少，导致细胞毒性 CD8 T 细胞的功能激活。总之，我们的研究结果表明，TAMpepK 可以通过靶向 M2 样 TAMs 成为抑制乳腺癌转移的新型治疗剂。
