Tumor-initiating cells escape tumor immunity via CCL8 from tumor-associated macrophages in mice
Shuang Chen1, Chensong Huang1, Kang Li1
1Department 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.
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-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.
Insights
Tumor-initiating cells (TICs) evade immune attack through GAS6/AXL/MERTK signaling with macrophages. Inhibiting this pathway, particularly CCL8, restores anti-tumor immunity and enhances immunotherapy.
Area of Science:
- Cancer Biology
- Immunology
- Molecular Oncology
Background:
- Tumor-initiating cells (TICs) drive cancer progression and immune evasion.
- Mechanisms by which TICs escape immune surveillance are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms of TIC immune escape.
- To identify therapeutic targets for overcoming TIC-mediated immunosuppression.
Main Methods:
- Single-cell RNA sequencing (scRNA-Seq) and lineage tracing.
- In vivo studies using chemical inhibitors and Axl/Mertk conditional double-KO (cDKO) mice.
- Analysis of growth arrest-specific 6/AXL receptor tyrosine kinase/MER proto-oncogene, tyrosine kinase (GAS6/AXL/MERTK) signaling pathways.
Main Results:
- Identified a WNT-activated subpopulation of malignant cells functioning as TICs.
- Discovered reciprocal interactions between TICs and immune-regulatory tumor-associated macrophages (Reg-TAMs) via GAS6/AXL/MERTK signaling.
- Demonstrated that inhibiting GAS6/AXL/MERTK signaling reactivates anti-tumor immunity and identified CCL8 as a key mediator suppressing Treg infiltration.
- Showed AXL/MERTK blockade sensitizes tumors to anti-programmed cell death 1 (anti-PD-1) therapy.
Conclusions:
- Elucidated a novel mechanism of TIC immune evasion involving GAS6/AXL/MERTK signaling and Reg-TAMs.
- Targeting the GAS6/AXL/MERTK pathway, including CCL8, offers a strategy to enhance anti-tumor immunity.
- Combined inhibition of TIC immune escape pathways with immunotherapy, like anti-PD-1, may overcome treatment resistance.
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