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Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy

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Abstract

Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%–50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

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Acknowledgements

This study was funded in part by research funding from the National Natural Science Foundation of China (Nos. 81830007, 82130004, 81600155, and 81670716), Clinical Research Plan of SHDC (No. 2020CR1032B), Shanghai Rising-Star Program (No. 19QA145600), Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (No. 2017YQ075), Talent (Class A) of Guangci Excellence Youth Plan (No. GCQN-2019-A16), Clinical Research Plan of Shanghai Hospital Development Center (No. SHDC2020CR1032B), Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (Nos. 20152206 and 20152208), China CAR-T Clinical Research Fund Project (No. CARTFR-05), and Samuel Waxman Cancer Research Foundation.

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Zixun Yan, Li Li, Di Fu, Wen Wu, Niu Qiao, Yaohui Huang, Lu Jiang, Pengpeng Xu, Shu Cheng, Li Wang & Weili Zhao

  2. Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China

    Depei Wu

  3. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China

    Yu Hu

  4. Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300070, China

    Huilai Zhang

  5. University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA

    Li Li, Sahin Lacin & Muharrem Muftuoglu

  6. Laboratory of Molecular Pathology, Pôle de Recherches Sino-Français en Science du Vivant et Génomique, Shanghai, 200025, China

    Weili Zhao

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  1. Zixun Yan
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Correspondence to Weili Zhao.

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Zixun Yan, Li Li, Di Fu, Wen Wu, Niu Qiao, Yaohui Huang, Lu Jiang, Depei Wu, Yu Hu, Huilai Zhang, Pengpeng Xu, Shu Cheng, Li Wang, Sahin Lacin, Muharrem Muftuoglu, and Weili Zhao have no relevant conflicts of interest to disclose. All procedures followed were in accordance with the ethical standards of Ethics Committee, Ruijin Hospital (approval No. 2018-76) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

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Yan, Z., Li, L., Fu, D. et al. Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy. Front. Med. 17, 699–713 (2023). https://doi.org/10.1007/s11684-022-0972-8

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