Chen Shuang, Huang Chensong, Li Kang, Cheng Maosheng, Zhang Caihua, Xiong Jianqi, Tian Guoli, Zhou Ruoxing, Ling Rongsong, Wang Xiaochen, Xiong Gan, Zhang Zhihui, Ma Jieyi, Zhu Yan, Zhou Bin, Peng Liang, Peng Zhenwei, Li Heping, Chen Demeng
Department of Otorhinolaryngology, Department of Medical Oncology, Department of Pancreato-Biliary Surgery, Department of Radiation Oncology, Cancer Center, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University (FAHSYSU), Guangzhou, China.
Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
J Clin Invest. 2025 Jan 7;135(5):e180893. doi: 10.1172/JCI180893.
Tumor-initiating cells (TICs) play a key role in cancer progression and immune escape. However, how TICs evade immune elimination remains poorly characterized. Combining single-cell RNA-Seq (scRNA-Seq), dual-recombinase-based lineage tracing, and other approaches, we identified a WNT-activated subpopulation of malignant cells that act as TICs in vivo. We found intensive reciprocal interactions between TICs and immune-regulatory tumor-associated macrophages (Reg-TAMs) via growth arrest-specific 6/AXL receptor tyrosine kinase/MER proto-oncogene, tyrosine kinase (GAS6/AXL/MERTK) signaling pathways, which facilitated the immune escape of TICs. In this study, we used chemical inhibitors and Axl/Mertk conditional double-KO (cDKO) mice to demonstrate that inhibiting the interaction between TIC-derived GAS6 and AXL/MERTK in Reg-TAMs reactivated antitumor immune responses. We identified CCL8 as a critical mediator of the GAS6/AXL/MERTK pathway, primarily by inhibiting Treg infiltration into the tumor. Furthermore, the AXL/MERTK signaling blockade sensitized tumor cells to anti-programmed cell death 1 (anti-PD-1) treatment. Thus, we elucidated a detailed mechanism by which TICs evade tumor immunity, providing insights into strategies to eradicate TICs that escape conventional immunotherapy.
肿瘤起始细胞（TICs）在癌症进展和免疫逃逸中起关键作用。然而，TICs如何逃避免疫清除仍不清楚。结合单细胞RNA测序（scRNA-Seq）、基于双重组酶的谱系追踪和其他方法，我们鉴定出一个WNT激活的恶性细胞亚群，其在体内充当TICs。我们发现TICs与免疫调节性肿瘤相关巨噬细胞（Reg-TAMs）之间通过生长停滞特异性6/AXL受体酪氨酸激酶/MER原癌基因酪氨酸激酶（GAS6/AXL/MERTK）信号通路存在强烈的相互作用，这促进了TICs的免疫逃逸。在本研究中，我们使用化学抑制剂和Axl/Mertk条件性双敲除（cDKO）小鼠来证明，抑制Reg-TAMs中TIC衍生的GAS6与AXL/MERTK之间的相互作用可重新激活抗肿瘤免疫反应。我们确定CCL8是GAS6/AXL/MERTK通路的关键介质，主要是通过抑制调节性T细胞（Treg）浸润到肿瘤中。此外，AXL/MERTK信号阻断使肿瘤细胞对抗程序性细胞死亡蛋白1（抗PD-1）治疗敏感。因此，我们阐明了TICs逃避肿瘤免疫的详细机制，为根除逃避传统免疫疗法的TICs的策略提供了见解。
