Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy.
10.1007/s11684-022-0972-8
- Author:
Zixun YAN
1
;
Li LI
1
;
Di FU
1
;
Wen WU
1
;
Niu QIAO
1
;
Yaohui HUANG
1
;
Lu JIANG
1
;
Depei WU
2
;
Yu HU
3
;
Huilai ZHANG
4
;
Pengpeng XU
1
;
Shu CHENG
1
;
Li WANG
1
;
Sahin LACIN
5
;
Muharrem MUFTUOGLU
5
;
Weili ZHAO
6
Author Information
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.
2. Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215000, China.
3. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China.
4. Tianjin Medical University Cancer Institute & Hospital, Tianjin, 300070, China.
5. University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA.
6. 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. zhao.weili@yahoo.com.
- Publication Type:Journal Article
- Keywords:
anti-CD19 chimeric antigen receptor T;
diffuse large B cell lymphoma;
immunotherapy;
metabolism;
tumor microenvironment;
tumor-associated macrophage
- From:
Frontiers of Medicine
2023;17(4):699-713
- CountryChina
- Language:English
-
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.
