肿瘤相关巨噬细胞分泌CCL18诱导乳腺癌赫赛汀耐药的机制

HER-2 positive is a kind of strongly invasive, short lifetime molecular subtype of breast cancer. Trastuzumab is the specificity of therapeutic agents against the HER-2 target 。But trastusumab resistance is a hot issues in recent years. Tumor associated macrophages are a fundamental part of tumor microenvironments. TAMs secrete large amounts of CCL18, which has an important role in promoting breast cancer metastasis. In preliminary experiment，we found local high-infiltrating macrophages in tumor tissues has relationship with poor response to trastusumab treatment. As a result, this project intends to research the relationship between CCL18 secreted by tumor associated macrophages and trastusumab resistance, and further clarify the molecular mechanism of this relationship。Provide a new approach by targeted in regulating the tumor microenvironment to enhance trastusumab treatment effect.

赫赛汀是目前针对HER-2+乳腺癌最重要的靶向治疗药物，赫赛汀耐药是近年的研究热点。我们前期实验发现肿瘤相关巨噬细胞（ Tumor associated macrophages ，TAMs）通过趋化因子受体1818（Chemokine (C–C motif) ligand 18， CCL18）促进乳腺癌转移。我们预实验发现术前穿刺标本TAMs越多，患者对赫赛汀的术前化疗反应越差。体外实验发现TAMs通过分泌CCL18，激活PI3K和ERK通路，从而诱导HER-2+乳腺癌细胞赫赛汀耐药。在这基础上，本研究进一步探索其分子机制，在体内外模型中通过拮抗节点分子逆转TAMs诱导乳腺癌赫赛汀耐药。本研究有助进一步明确炎癌互动关系，为逆转肿瘤靶向治疗耐药提供新思路。

抗体依赖的细胞毒性(ADCC)和抗体依赖的细胞吞噬(ADCP)在对抗肿瘤治疗性抗体的疗效有重要作用。我们在此报告了一个意外的发现，在乳腺癌和淋巴瘤中，ADCP后巨噬细胞抑制NK细胞介导的ADCC和T细胞介导的细胞毒性。从机制上讲，AIM2通过FcγR信号在ADCP之后被召集入吞噬体，并通过破坏的吞噬体膜感知被吞噬的肿瘤DNA而被激活，随后上调PD-L1和IDO并导致免疫抑制。联合抗Her-2抗体和PD-L1、IDO抑制剂治疗可增强小鼠模型的抗肿瘤免疫和抗her2治疗效果。此外，新辅助曲妥珠单抗治疗可显著上调HER2乳腺癌患者肿瘤相关巨噬细胞(TAMs)中的PD-L1和IDO，这与曲妥珠单抗不良反应相关。总的来说，我们的发现揭示了ADCP巨噬细胞在癌症免疫抑制中的有害作用，并提示治疗性抗体加免疫检查点阻滞可能在癌症治疗中提供协同效应。