2. Academic Validation
  3. LW-213 induces immunogenic tumor cell death via ER stress mediated by lysosomal TRPML1

LW-213 induces immunogenic tumor cell death via ER stress mediated by lysosomal TRPML1

  • Cancer Lett. 2023 Oct 6:216435. doi: 10.1016/j.canlet.2023.216435.
Meng-Yuan Zhu 1,  Ting Wang 1,  Hai-di Wang 1,  Hong-Zheng Wang 1,  Hong-Yu Chen 1,  Shuai Zhang 2,  Yong-Jian Guo 1,  Hui Li 3,  Hui Hui 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China.
  • 2 The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People's Republic of China.
  • 3 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China. Electronic address: gj_hog@163.com.
  • 4 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China. Electronic address: moyehh@163.com.
PMID: 37806516 DOI: 10.1016/j.canlet.2023.216435
Abstract

Dying tumor cells release biological signals that exhibit antigenicity, activate cytotoxic T lymphocytes, and induce immunogenic cell death (ICD), playing a key role in immune surveillance. We demonstrate that the flavonoid LW-213 activates endoplasmic reticulum stress (ERS) in different tumor cells and that the lysosomal Calcium Channel TRPML1 mediates the ERS process in human cellular lymphoma Hut-102 cells. Apoptotic tumor cells induced by ERS often possess immunogenicity. Tumor cells treated with LW-213 exhibit damage-associated molecular patterns (DAMPs), including calreticulin translocation to the plasma membrane and extracellular release of ATP and HMGB1. When co-cultured with antigen-presenting cells (APCs), LW-213-treated tumor cells activated APCs. Two groups of C57BL/6J mice were inoculated with Lewis cells: a "vaccine group", which demonstrated that LW-213-treated tumor cells promote the maturation of dendritic cells and increase CD8+ T cells infiltration in the tumor microenvironment and a "pharmacodynamic group", treated with a combination of LW-213 and PD1/PD-L1 inhibitor (BMS-1), which reduced tumor growth and significantly prolonged the survival time of mice in the "pharmacodynamic group". Therefore, LW-213 can be developed as a novel ICD inducer, providing a new concept for antitumor immunotherapy.

Keywords

Calcium signaling; DC; Damage associated molecular patterns (DAMPs); Immunotherapy; Lysosome; PD1/PD-L1.

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