AXL抗体和AXL-ADC通过将AXL靶向肿瘤 - 内膜上皮 - 间质转变和与肿瘤相关的M2样巨噬细胞中介导抗肿瘤功效
AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage
影响因子:8.40000
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2023 Jun
作者:
Jin-Peng Pei, Yue Wang, Lan-Ping Ma, Xin Wang, Liang Liu, Yu Zhang, Rui Jin, Zhi-Qiang Ren, Yan Deng, Jing-Kang Shen, Tao Meng, Ker Yu
摘要
受体酪氨酸激酶AXL是癌症复发的新兴驱动力，而其分子机制尚不清楚。在这项研究中，我们研究了AXL如何调节非小细胞肺癌（NSCLC）和三阴性乳腺癌（TNBC）的疾病进展和预后不良。我们从TCGA数据集进行了AXL转录组分析，发现NSCLC和TNBC的AXL表达显着升高，与预后不良，上皮 - 间质转变（EMT）和易受免疫耐受性肿瘤微环境（TME）相关。用两种独立的AXL抗体（命名为抗AXL和AXL02）敲低AXL或处理，在AXL-HIGH表达NSCLC和TNBC细胞系中，均减少了细胞迁移和EMT。在4T1 TNBC的小鼠模型中，抗AXL抗体的给药基本上抑制了肺转移的形成和生长，并伴随着下游信号激活，EMT和增殖指数的降低，以及增加的凋亡和激活的抗肿瘤免疫。我们发现AXL在肿瘤结节渗透的M2巨噬细胞中大量激活。特定的抗AXL抗体在体外阻断了骨髓来源的巨噬细胞（BMDM）M2极化。除肿瘤细胞外，靶向M2-巨噬细胞中AXL的靶向实质上抑制了CSF-1的产生，并消除了TME中的M2-巨噬细胞，从而导致先天性和适应性免疫的协调增强，反映了M1样巨噬细胞，成熟的树突状细胞，细胞毒素T细胞和B细胞。我们使用特定于特定的共轭平台生成了一个新颖的人源化AXL-ADC（AXL02-MMAE）。 AXL02-MMAE针对一组AXL高表达肿瘤细胞系（IC50 <0.1 nmol/L）施加了有效的细胞毒性，并抑制了多种NSCLC和神经胶质瘤肿瘤的体内生长（最小效率剂量<1 mg/kg）。与化学疗法相比，AXL02-MMAE在消除大尺寸肿瘤方面具有出色的功效，消除了AXL-H肿瘤细胞依赖性的M2巨噬细胞浸润，并具有强劲的炎性巨噬细胞和成熟的树突状细胞的积累。我们的结果支持靶向AXL靶向的治疗，用于治疗晚期NSCLC和TNBC。
Abstract
The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence, while its molecular mechanism remains unclear. In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We performed AXL transcriptome analysis from TCGA datasets, and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis, epithelial-mesenchymal transition (EMT) and immune-tolerant tumor microenvironment (TME). Knockdown of AXL or treatment with two independent AXL antibodies (named anti-AXL and AXL02) all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines. In a mouse model of 4T1 TNBC, administration of anti-AXL antibody substantially inhibited lung metastases formation and growth, accompanied by reduced downstream signaling activation, EMT and proliferation index, as well as an increased apoptosis and activated anti-tumor immunity. We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages. A specific anti-AXL antibody blocked bone marrow-derived macrophage (BMDM) M2-polarization in vitro. Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME, leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages, mature dendritic cells, cytotoxic T cells and B cells. We generated a novel and humanized AXL-ADC (AXL02-MMAE) employing a site-specific conjugation platform. AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines (IC50 < 0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors (a minimum efficacy dose<1 mg/kg). Compared to chemotherapy, AXL02-MMAE achieved a superior efficacy in regressing large sized tumors, eliminated AXL-H tumor cell-dependent M2-macrophage infiltration with a robust accumulation of inflammatory macrophages and mature dendritic cells. Our results support AXL-targeted therapy for treatment of advanced NSCLC and TNBC.