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

Ma, Jing1,2; Chen, Yutong3; Li, Tao1,2; Cao, Yi1,2; Hu, Bin1,2; Liu, Yuru1,2; Zhang, Youran1,2; Li, Xiaoyan1,2; Liu, Jianing1,2; Zhang, Wei1,2; Niu, Hanjing1,2; Gao, Jinhua1,2; Zhang, Zhongze1,2; Yue, Kexin1,2; Wang, Jiajia2; Bao, Guochen4; Wang, Chaojie5; Wang, Peng George6; Zou, Taotao7; Xie, Songqiang1

2024-06-14

10.1038/s41388-024-03043-y

ONCOGENE   影响因子和分区

0950-9232

1476-5594

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-beta 1 (TGF-beta 1). However, the absence of a specific surface marker makes inhibiting the production of active TGF-beta 1 to specifically deplete human Tregs but not other cell types a challenge. TGF-beta 1 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-beta 1 for remodeling the tumor microenvironment. Mechanistically, NPt is stored in Treg lysosome to inhibit TRAF3IP3-meditated GARP/TGF-beta 1 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-beta 1 signaling pathway. In addition to expose a previously undefined divergent lysosomal metabolic program-meditated GARP/TGF-beta 1 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.

SCI

英语

其他

Second batch of provincial science and technology research and development plan joint funds[225200810116] ; China Postdoctoral Foundation[2023T160190] ; China Postdoctoral Science Foundation[2021M701089] ; Key Scientific Research Projects in Henan Colleges and Universities[22A350002] ; Natural Science Foundation of Henan Province[232300420047] ; Key scientific research projects of universities in Henan province["222102310402","222102310216"] ; Key Program "New Drug Creation" of Guangdong Key Research, Development Plan[2019B020202001]

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

Biochemistry & Molecular Biology ; Oncology ; Cell Biology ; Genetics & Heredity

WOS:001217015200001

SPRINGERNATURE

MOLECULAR BIOLOGY & GENETICS

Web of Science

1.Henan Univ, Huaihe Hosp Henan Univ, Acad Adv Interdisciplinary Studies, Sch Pharm,Inst Chem Biol,State Key Lab Antiviral D, Kaifeng 475004, Henan, Peoples R China
2.Henan Univ, Joint Natl Lab Antibody Drug Engn, Kaifeng 475004, Henan, Peoples R China
3.South China Univ Technol, Guangzhou 511442, Guangdong, Peoples R China
4.Univ Technol Sydney, Inst Biomed Mat & Devices IBMD, Fac Sci, Sydney, NSW, Australia
5.Henan Univ, Key Lab Nat Med & Immuno Engn, Kaifeng 475004, Peoples R China
6.Southern Univ Sci & Technol, Sch Med, Shenzhen 518005, Guangdong, Peoples R China
7.Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangdong Key Lab Chiral Mol & Drug Discovery, Guangzhou 510006, Peoples R China

Ma, Jing,Chen, Yutong,Li, Tao,et al. Suppression of lysosome metabolism-meditated GARP/TGF-β1 complexes specifically depletes regulatory T cells to inhibit breast cancer metastasis[J]. ONCOGENE,2024,43(25).

Ma, Jing.,Chen, Yutong.,Li, Tao.,Cao, Yi.,Hu, Bin.,...&Xie, Songqiang.(2024).Suppression of lysosome metabolism-meditated GARP/TGF-β1 complexes specifically depletes regulatory T cells to inhibit breast cancer metastasis.ONCOGENE,43(25).

Ma, Jing,et al."Suppression of lysosome metabolism-meditated GARP/TGF-β1 complexes specifically depletes regulatory T cells to inhibit breast cancer metastasis".ONCOGENE 43.25(2024).