Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival
Targeted delivery of proapoptotic peptides to tumor-associated macrophages improves survival
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DOI：
10.1073/pnas.1312197110
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发表时间：
2013-10-01
影响因子：
11.1
通讯作者：
Pun, Suzie H.
中科院分区：
文献类型：
--
作者：
Cieslewicz, Maryelise;Tang, Jingjing;Pun, Suzie H.
目前大多数癌症疗法都集中在杀死恶性细胞，但这些细胞通常在遗传上不稳定，并且可能对化疗产生抗药性。肿瘤相关巨噬细胞（TAM）通过促进血管生成和肿瘤细胞生长以及通过抑制适应性免疫应答来促进疾病进展。因此，TAM是辅助抗癌治疗的潜在靶点。然而，常驻巨噬细胞对宿主防御至关重要，并且TAM的优先消融仍然具有挑战性。巨噬细胞活化被广泛分类为经典活化或M1，或者活化或M2，并且肿瘤微环境中的TAM已显示采用抗炎的M2样表型。迄今为止，还没有用于TAM的特异性分子靶向的方法。在这项工作中，我们报告发现了一个独特的肽序列，M2pep，确定使用消减噬菌体生物淘选策略对整个细胞。该肽优先结合鼠M2细胞，包括TAM，对其他白细胞具有低亲和力。共聚焦成像证实了尾静脉注射后M2pep在体内TAM中的积累。最后，尾静脉注射具有促凋亡肽的M2pep融合肽延迟死亡率并选择性地减少M2样TAM群体。因此，这项工作描述了一种分子靶向构建的鼠TAM，并提供了这种方法作为抗癌治疗的概念证明。此外，M2pep是用于鼠M2巨噬细胞鉴定和用于在涉及M2细胞的其他鼠疾病模型中调节M2巨噬细胞的有用工具。
Most current cancer therapies focus on killing malignant cells, but these cells are often genetically unstable and can become resistant to chemotherapy. Tumor-associated macrophages (TAMs) facilitate disease progression by promoting angiogenesis and tumor cell growth, as well as by suppressing the adaptive immune response. TAMs are therefore potential targets for adjuvant anticancer therapies. However, resident macrophages are critical to host defense, and preferential ablation of TAMs remains challenging. Macrophage activation is broadly categorized as classically activated, or M1, and alternatively activated, or M2, and TAMs in the tumor microenvironment have been shown to adopt the anti-inflammatory, M2-like phenotype. To date, there are no methods for specific molecular targeting of TAMs. In this work, we report the discovery of a unique peptide sequence, M2pep, identified using a subtractive phage biopanning strategy against whole cells. The peptide preferentially binds to murine M2 cells, including TAMs, with low affinity for other leukocytes. Confocal imaging demonstrates the accumulation of M2pep in TAMs in vivo after tail vein injection. Finally, tail vein injection of an M2pep fusion peptide with a proapoptotic peptide delays mortality and selectively reduces the M2-like TAM population. This work therefore describes a molecularly targeted construct for murine TAMs and provides proof of concept of this approach as an anticancer treatment. In addition, M2pep is a useful tool for murine M2 macrophage identification and for modulating M2 macrophages in other murine models of disease involving M2 cells.