Advertisement

ResearchIn-Press PreviewOncology Open Access | 10.1172/JCI180893

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

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 and Demeng Chen1

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Chen, S. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Huang, C. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Li, K. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Cheng, M. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Zhang, C. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Xiong, J. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Tian, G. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Zhou, R. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Ling, R. in: JCI | PubMed | Google Scholar |

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Wang, X. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Xiong, G. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Zhang, Z. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Ma, J. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Zhu, Y. in: JCI | PubMed | Google Scholar |

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Zhou, B. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Peng, L. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Peng, Z. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Li, H. in: JCI | PubMed | Google Scholar

1Department of Medical Oncology; Department of Pancreato-Biliary Surgery; De, Center for Translational Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China

2Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China

3Department of Medical Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

4State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry an, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China

5Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China

Find articles by Chen, D. in: JCI | PubMed | Google Scholar

Published January 7, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI180893.
Copyright © 2025, Chen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 7, 2025 - Version history
View PDF
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.

Supplemental material

View Table S1

View Table S2

View Table S3

View Unedited blot and gel images

Version history
  • Version 1 (January 7, 2025): In-Press Preview
Advertisement
Advertisement