Suppression of Lysosome Metabolism-meditated GARP/TGF-β1 Complexes Specifically Depletes Regulatory T Cells to Inhibit Breast Cancer Metastasis

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2024 May 2

PMID 38698265

Authors

Jing Ma

Yutong Chen

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

Guochen Bao

Chaojie Wang

Peng George Wang

Taotao Zou

Songqiang Xie

Affiliations

Soon will be listed here.

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.

Citing Articles

Treg Cell Therapeutic Strategies for Breast Cancer: Holistic to Local Aspects.

Zhang H, Felthaus O, Eigenberger A, Klein S, Prantl L Cells. 2024; 13(18.

PMID: 39329710 PMC: 11429654. DOI: 10.3390/cells13181526.

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