Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy.
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, Weili Zhao
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引用次数: 4
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.
Frontiers of MedicineONCOLOGYMEDICINE, RESEARCH & EXPERIMENTAL&-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
18.30
自引率
0.00%
发文量
800
期刊介绍:
Frontiers of Medicine is an international general medical journal sponsored by the Ministry of Education of China. The journal is jointly published by the Higher Education Press and Springer. Since the first issue of 2010, this journal has been indexed in PubMed/MEDLINE.
Frontiers of Medicine is dedicated to publishing original research and review articles on the latest advances in clinical and basic medicine with a focus on epidemiology, traditional Chinese medicine, translational research, healthcare, public health and health policies.