title: IL-2 augments the therapeutic efficacy of adoptively transferred B cells which directly kill tumor cells via the CXCR4/CXCL12 and perforin pathways.
abstract: 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.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|The No.1 People's Hospital of Hefei, Hefei, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|Hubei Province Stem Cell Research & Appling Center, Wuhan Union Hospital, Wuhan, China.|Current address: Fuda Cancer Hospital, Jinan University School of Medicine and Fuda Cancer Institute, Guangzhou, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Tao
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|Hubei Province Stem Cell Research & Appling Center, Wuhan Union Hospital, Wuhan, China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|Department of General Surgery, Tongji Hospital of Tongji University, Shanghai, China.
authors.forename: Quanning
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|Department of Oncology, Wuhan University, Renmin Hospital, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|The No.1 People's Hospital of Hefei, Hefei, China.
authors.forename: Leiming
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.|Department of Biotherapy, Tianjin University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: The No.1 People's Hospital of Hefei, Hefei, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The No.1 People's Hospital of Hefei, Hefei, China.
authors.forename: Yangyi
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Hubei Province Stem Cell Research & Appling Center, Wuhan Union Hospital, Wuhan, China.
authors.forename: Shiang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Biotherapy, Tianjin University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key laboratory of Cancer Immunology and Biotherapy, Tianjin, China.
authors.forename: Xiubao
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Lundy
authors.affiliation: The No.1 People's Hospital of Hefei, Hefei, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Dai
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Qiao
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Alfred E
authors.initials: AE
authors.lastname: Chang
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D001596:Benzylamines; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis; D000080027:Cyclams; D003602:Cytotoxicity, Immunologic; D005260:Female; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D006801:Humans; D056724:Immunity, Humoral; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000627:therapeutic use*; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000628:therapy*; D051379:Mice; D054353:Perforin / Q000276:immunology / Q000627:therapeutic use*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism
chemical_list: D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D007376:Interleukin-2; D019718:Receptors, CXCR4; D015375:Receptors, Interleukin-2; D054353:Perforin; D016753:Interleukin-10; C088327:plerixafor
keywords: B cells; CXCR4/CXCL12; IL-2; adoptive immunotherapy; perforin