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Suppression of lysosome metabolism-meditated GARP/TGF-β1 complexes specifically depletes regulatory T cells to inhibit breast cancer metastasis

Oncogene (2024)Cite this article

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Abstract

Regulatory T cells (Tregs) prevent autoimmunity and contribute to cancer progression. They exert contact-dependent inhibition of immune cells through the production of active transforming growth factor-β1 (TGF-β1). However, the absence of a specific surface marker makes inhibiting the production of active TGF-β1 to specifically deplete human Tregs but not other cell types a challenge. TGF-β1 in an inactive form binds to Tregs membrane protein Glycoprotein A Repetitions Predominant (GARP) and then activates it via an unknown mechanism. Here, we demonstrated that tumour necrosis factor receptor-associated factor 3 interacting protein 3 (TRAF3IP3) in the Treg lysosome is involved in this activation mechanism. Using a novel naphthalenelactam-platinum-based anticancer drug (NPt), we developed a new synergistic effect by suppressing ATP-binding cassette subfamily B member 9 (ABCB9) and TRAF3IP3-mediated divergent lysosomal metabolic programs in tumors and human Tregs to block the production of active GARP/TGF-β1 for remodeling the tumor microenvironment. Mechanistically, NPt is stored in Treg lysosome to inhibit TRAF3IP3-meditated GARP/TGF-β1 complex activation to specifically deplete Tregs. In addition, by promoting the expression of ABCB9 in lysosome membrane, NPt inhibits SARA/p-SMAD2/3 through CHRD-induced TGF-β1 signaling pathway. In addition to expose a previously undefined divergent lysosomal metabolic program-meditated GARP/TGF-β1 complex blockade by exploring the inherent metabolic plasticity, NPt may serve as a therapeutic tool to boost unrecognized Treg-based immune responses to infection or cancer via a mechanism distinct from traditional platinum drugs and currently available immune-modulatory antibodies.

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Scheme 1
Fig. 1: NPt preferentially accumulated in TNBC metastases in tumor bearing mice.
Fig. 2: NPt inhibits the production of active TGF-β1 by Tregs but not by other cell types to remarkably inhibit breast cancer metastasis in mice.
Fig. 3: TRAF3IP3 in lysosome-restricted GARP/TGF-β1 complexes specifically deplete human Tregs.
Fig. 4: ABCB9 in lysosome contributes to CHRD-induced TGF-β1 signaling pathway in NPt-treated breast cancer cells.

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Acknowledgements

This work was supported by the second batch of provincial science and technology research and development plan joint funds (225200810116), the 16th batch of special grant (station) from China Postdoctoral Foundation (2023T160190), the China Postdoctoral Science Foundation (Grant 2021M701089), Key Scientific Research Projects in Henan Colleges and Universities (Grant No. 22A350002), Natural Science Foundation of Henan Province (232300420047), the key scientific research projects of universities in Henan province (222102310402 and 222102310216), Key Program “New Drug Creation” of Guangdong Key Research, Development Plan (No.2019B020202001), and the Youth Promotion Project of Zhongzhou Laboratory for Integrative Biology.

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  1. These authors contributed equally: Jing Ma, Yutong Chen, Tao Li.

Authors and Affiliations

  1. School of Pharmacy, The Zhongzhou Laboratory for Integrative Biology, Huaihe Hospital of Henan University, Institute of Chemical Biology, Academy for Advanced Interdisciplinary Studies, Henan Province Engineering Research Center of High Value Utilization to Natural Medical Resource in Yellow River Basin, State Key Laboratory of Antiviral Drugs, Henan University, Kaifeng, Henan, 475004, China

    Jing Ma, Tao Li, Yi Cao, Bin Hu, Yuru Liu, Youran Zhang, Xiaoyan Li, Jianing Liu, Wei Zhang, Hanjing Niu, Jinhua Gao, Zhongze Zhang, Kexin Yue & Songqiang Xie

  2. Joint National Laboratory for Antibody Drug Engineering, Henan University, Kaifeng, Henan, 475004, China

    Jing Ma, Tao Li, Yi Cao, Bin Hu, Yuru Liu, Youran Zhang, Xiaoyan Li, Jianing Liu, Wei Zhang, Hanjing Niu, Jinhua Gao, Zhongze Zhang, Kexin Yue & Jiajia Wang

  3. South China University of Technology, Guangzhou, Guangdong, 511442, China

    Yutong Chen

  4. Institute for Biomedical Materials and Devices (IBMD), Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia

    Guochen Bao

  5. The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, 475004, China

    Chaojie Wang

  6. School of Medicine, The Southern University of Science and Technology, Shenzhen, Guangdong, 518005, China

    Peng George Wang

  7. Guangdong Key Laboratory of Chiral Molecule and Drug Discovery School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China

    Taotao Zou

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Contributions

The study was instructed by all authors. CYT and TL collected the primary literature and performed the major work and drafted the manuscript. CY and HB prepared the figures. CY made critical revisions and commentary on this manuscript and coordinated with all the authors. ZYR, LXY, LYR, and YKX made proper and necessary investigations and validation of this work. ZZZ and ZW provided partly the structures of mentioned chemicals. BGC, WP, WCJ, XSQ, and MJ directed and guided the whole work. MJ obtained the funding. All authors read and approved the final manuscript.

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Correspondence to Jiajia Wang or Songqiang Xie.

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Ma, J., Chen, Y., Li, T. et al. Suppression of lysosome metabolism-meditated GARP/TGF-β1 complexes specifically depletes regulatory T cells to inhibit breast cancer metastasis. Oncogene (2024). https://doi.org/10.1038/s41388-024-03043-y

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