IL-2 augments the therapeutic efficacy of adoptively transferred B cells which directly kill tumor cells via the CXCR4/CXCL12 and perforin pathways
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Yang Xia1,2,*, Huimin Tao1,3,8,*, Yangyang Hu1,3,*, Quanning Chen1,4,*, Xin Chen1,5, Leiming Xia1,2, Li Zhou1,6, Yi Wang2, Yangyi Bao2, Shiang Huang3, Xiubao Ren6, Steven K. Lundy7, Fu Dai2,**, Qiao Li1,**, Alfred E. Chang1,**
1Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
2The No.1 People’s Hospital of Hefei, Hefei, China
3Hubei Province Stem Cell Research & Appling Center, Wuhan Union Hospital, Wuhan, China
4Department of General Surgery, Tongji Hospital of Tongji University, Shanghai, China
5Department of Oncology, Wuhan University, Renmin Hospital, Wuhan, China
6Department of Biotherapy, Tianjin University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Immunology and Biotherapy, Tianjin, China
7Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
8Current address: Fuda Cancer Hospital, Jinan University School of Medicine and Fuda Cancer Institute, Guangzhou, China
*These authors have contributed equally to this work
**Joint senior authors
Qiao Li, email: firstname.lastname@example.org
Alfred E. Chang, email: email@example.com
Fu Dai, email: firstname.lastname@example.org
Keywords: B cells, adoptive immunotherapy, IL-2, CXCR4/CXCL12, perforin
Abbreviations: TDLN, tumor-draining lymph node; CM, complete medium; s.c., subcutaneous; i.v., intravenously; i.p., intraperitoneal
Received: December 06, 2015 Accepted: July 26, 2016 Published: August 09, 2016
We previously reported that antitumor B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL-10. In this study, we defined additional mechanisms involved in B cell antitumor immunity. Administration of IL-2 significantly augmented the therapeutic efficacy of adoptively transferred tumor-draining lymph node (TDLN) B cells which express IL- 2R. Culture supernatant of purified B splenocytes harvested from the mice that received adoptive transfer of 4T1 TDLN B cells plus IL-2 administration produced larger amounts of IgG which bound to 4T1, resulting in 4T1 lysis. Furthermore, we detected CXCR4 expression on 4T1 TDLN B cells, and 4T1 tumor cells produced its ligand CXCL12. Transwell experiments demonstrated the chemoattraction of CXCR4-expressing 4T1 TDLN B cells towards CXCL12- producing 4T1 cells. Blockade of CXCR4 using a CXCR4-specific inhibitor, AMD3100, significantly reduced the killing of 4T1 tumor cells by 4T1 TDLN B cells. Blockade of FasL and CXCR4 concurrently inhibited B cell-mediated direct killing of tumor cells in an additive manner, indicating that both Fas/FasL and CXCL12/CXCR4 pathways are involved in the direct killing of 4T1 cells by 4T1 TDLN B cells. TDLN B cells produced perforin. Additional transwell experiments showed that effector B cells could directly kill tumor cells in cell-cell contact via the Fas/FasL and CXCR4/CXCL12 pathways as well as perforin, while without cell contact, perforin secreted by B cells led to tumor cell cytotoxicity. These findings underscore the diversity of function by which B cells can play an important role in the host immune response to tumor.
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