LRP1 induces anti-PD-1 resistance by modulating the DLL4-NOTCH2-CCL2 axis and redirecting M2-like macrophage polarisation in bladder cancer.

Autor: Lin H; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Fu L; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Zhou X; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Yu A; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Chen Y; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Liao W; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Shu G; Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, China., Zhang L; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Tan L; Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China., Liang H; Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China., Wang Z; Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China., Deng Q; Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China., Wang J; Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China., Jin M; Department of Urology, Affiliated Longhua People's Hospital, Southern Medical University, Shenzhen, Guangdong, China., Chen Z; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Wei J; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Cao J; Department of Urology, Jiangmen Central Hospital, Haibang Street 23, Pengjiang District, Jiangmen, 529030, Guangdong Province, China., Chen W; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Li X; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: 13556162320@139.com., Li P; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: lipj25@mail.sysu.edu.cn., Lu J; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: lujun7@mail.sysu.edu.cn., Luo J; Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. Electronic address: luojunh@mail.sysu.edu.cn.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2024 Jul 01; Vol. 593, pp. 216807. Date of Electronic Publication: 2024 Mar 08.
DOI: 10.1016/j.canlet.2024.216807
Abstrakt: The tumour microenvironment (TME) drives bladder cancer (BLCA) progression. Targeting the TME has emerged as a promising strategy for BLCA treatment in recent years. Furthermore, checkpoint blockade therapies are only beneficial for a minority of patients with BLCA, and drug resistance is a barrier to achieving significant clinical effects of anti-programmed cell death protein-1 (PD-1)/programmed death protein ligand-1 (PD-L1) therapy. In this study, higher low-density lipoprotein receptor-related protein 1 (LRP1) levels were related to a poorer prognosis for patients with various cancers, including those with higher grades and later stages of BLCA. Enrichment analysis demonstrated that LRP1 plays a role in the epithelial-mesenchymal transition (EMT), NOTCH signalling pathway, and ubiquitination. LRP1 knockdown in BLCA cells delayed BLCA progression both in vivo and in vitro. Furthermore, LRP1 knockdown suppressed EMT, reduced DLL4-NOTCH2 signalling activity, and downregulated M2-like macrophage polarisation. Patients with BLCA and higher LRP1 levels responded weakly to anti-PD-1 therapy in the IMvigor210 cohort. Moreover, LRP1 knockdown enhanced the therapeutic effects of anti-PD-1 in mice. Taken together, our findings suggest that LRP1 is a potential target for improving the efficacy of anti-PD-1/PD-L1 therapy by preventing EMT and M2-like macrophage polarisation by blocking the DLL4-NOTCH2 axis.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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