CD40-activated B cells contribute to mesothelioma tumor regression

被引:41
作者
Jackaman, Connie [2 ]
Cornwall, Scott [1 ,3 ,4 ]
Graham, Peter Thomas [1 ,3 ,4 ]
Nelson, Delia Jane [1 ,2 ,3 ,4 ]
机构
[1] Curtin Univ Technol, Sch Biomed Sci, Immunol & Canc Grp, Perth, WA 6102, Australia
[2] Univ Western Australia, Queen Elizabeth II Med Ctr, Sch Med & Pharmacol, Perth, WA 6009, Australia
[3] Curtin Univ Technol, Western Australia Biomed Res Inst, Perth, WA 6102, Australia
[4] Curtin Univ Technol, Curtin Hlth Innovat Res Inst, Perth, WA 6102, Australia
关键词
tumor immunity; B cells; cytotoxic T cells; agonist anti-CD40 antibody; tumor targeting; CYTOKINE GENE-THERAPY; DRAINING LYMPH-NODES; T-CELLS; IMMUNOLOGICAL ENHANCEMENT; MALIGNANT MESOTHELIOMA; HUMORAL IMMUNITY; CD40; ACTIVATION; DEPRIVED MICE; SOLID TUMORS; RESPONSES;
D O I
10.1038/icb.2010.88
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Targeting CD40, a member of the tumor necrosis factor superfamily, using agonist antibodies (Abs) produces dramatic antitumor effects. Indeed, high-dose intravenous anti-CD40 Ab 'licenses' dendritic cells (DCs) that instruct activated CD8(+) cytotoxic T cells to leave lymph nodes (LNs) and penetrate the mesothelioma tumor microenvironment. However, toxic side effects and the potential of an 'overwhelmed' immune response warrant an alternative approach. In this study, we show that injecting lower doses of anti-CD40 Ab directly into the tumor bed avoided toxic side effects and prolonged survival in 60% of mice, with most cured. Unexpectedly, DCs in tumors and LNs 'disappeared', CD8(+) tumor-specific T-cell numbers and function were not enhanced, and T cells did not infiltrate regressing tumors. CD4(+) or CD8(+) depletion only marginally hindered anti-CD40 Ab efficacy implying another effector mechanism. B-cell numbers significantly increased in tumors, draining LNs and spleens during intratumoral anti-CD40 Ab treatment. CD40 targeting had no effect on splenic B-1 cells, obliterated marginal zone B cells and promoted follicular (FO) B-cell activity. Adoptive transfer of tumor antigen-experienced, CD40-activated B cells, or their immunoglobulin products, which recognized autoantigens on mesothelioma cells, protected against tumor challenge. Finally, studies using B-cell knockout mice showed that successful treatment of established tumors required the presence of B cells. Thus, these data suggest that CD40-activated FO B cells can become an important component of an effective antitumor immune response. Immunology and Cell Biology (2011) 89, 255-267; doi:10.1038/icb.2010.88; published online 13 July 2010
引用
收藏
页码:255 / 267
页数:13
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