Bendamustine-rituximab elicits dual tumoricidal and immunomodulatory responses via cGAS-STING activation in diffuse large B-cell lymphoma.

Autor:	Xiao R; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China.; Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China., Zhao W; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China., Lin W; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China., Xiao Y; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China., Ren J; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China., Zhou Y; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China., Meng W; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China mengwei_126@126.com bienguang1980@smu.edu.cn MJ090731@126.com., Bi E; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, Guangdong, China mengwei_126@126.com bienguang1980@smu.edu.cn MJ090731@126.com.; Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China., Jiang L; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China mengwei_126@126.com bienguang1980@smu.edu.cn MJ090731@126.com.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Nov 09; Vol. 12 (11). Date of Electronic Publication: 2024 Nov 09.
DOI:	10.1136/jitc-2024-009212
Abstrakt:	Background: Bendamustine-rituximab (BR) therapy stands out as a promising alternative for elderly patients with diffuse large B-cell lymphoma (DLBCL), demonstrating notable efficacy when conventional regimens pose challenges. Despite its clinical success, the intricate mechanisms underlying BR therapy have remained elusive. Methods: DLBCL cell lines were used to investigate the mechanism of BR therapy in vitro. RNA-seq and Western blot were used to explore the target pathways of BR therapy. STING was knocked out using Crispr-cas9 and inhibited using H-151 to investigate its role in BR therapy. Bulk RNA-seq and single-cell RNA-seq data from patients were analyzed to investigate the association between STING and pyroptosis pathways, validated using STING downregulated cells. Flow cytometry, transwell experiments and co-culture experiments were performed to investigate the inflammatory phenotype of DLBCL cells after BR treatment and its effect on T-cell recruitment and activation. Results: This study elucidates that BR elicits direct tumoricidal effects by promoting apoptosis and inducing cell cycle arrest. The synergistic impact with rituximab is further potentiated by complement addition, demonstrating the pivotal role of in vivo antibody-dependent cellular cytotoxicity. Moreover, our investigation reveals that, through a cGAS-STING-dependent pathway, prolonged exposure to BR induces pyroptosis in DLBCL cells. Activation of the cGAS-STING pathway by BR therapy triggers the release of inflammatory factors and upregulates major histocompatibility complex molecules, shaping an immunologically hot tumor microenvironment. Conclusions: This unique dual influence not only directly targets DLBCL cells but also engages the patient's immune system, paving the way for innovative combination therapies. The study provides comprehensive insights into the multifaceted actions of BR in DLBCL, offering a foundation for refined and personalized treatment strategies in elderly patients. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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