2. Academic Validation
  3. Tumor initiating cells escape tumor immunity via CCL8 from tumor-associated macrophages in mice

Tumor initiating cells escape tumor immunity via CCL8 from tumor-associated macrophages in mice

  • J Clin Invest. 2025 Jan 7:e180893. doi: 10.1172/JCI180893.
Shuang Chen 1,  Chen-Song Huang 1,  Kang Li 1,  Maosheng Cheng 1,  Caihua Zhang 1,  Jianqi Xiong 1,  Guoli Tian 2,  Ruoxing Zhou 1,  Rongsong Ling 1,  Xiaochen Wang 1,  Gan Xiong 3,  Zhihui Zhang 1,  Jieyi Ma 1,  Yan Zhu 1,  Bin Zhou 4,  Liang Peng 5,  Zhenwei Peng 1,  Heping Li 3,  Demeng Chen 1
Affiliations

Affiliations

  • 1 Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
  • 2 Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
  • 3 Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 4 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.
  • 5 Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China.
PMID: 39774471 DOI: 10.1172/JCI180893
Abstract

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 Sequencing (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 GAS6-AXL/MERTK signaling pathways, which facilitated the immune escape of TICs. Our study employed chemical inhibitors and Axl/Mertk conditional double knockout mice to demonstrate that inhibiting the interaction between TIC-derived GAS6 and Axl/MERTK in Reg-TAMs reactivated anti-tumor immune responses. We identified CCL8 as a critical mediator of the GAS6/Axl/MERTK pathway, primarily by inhibiting regulatory T cell (Treg) infiltration into the tumor. Furthermore, the Axl/MERTK signaling blockade sensitized tumor cells to 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.

Keywords

Cancer immunotherapy; Oncology.

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