期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 123, 期 4, 页码 1457-1474出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI65579
关键词
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资金
- NIHR Biomedical Research Centre
- CR UK/EPSRC/MRC/NIHR KCL/UCL Comprehensive Cancer Imaging Centre [C1519/A10331]
- Cancer Research UK [C30122/A11527, C16736/A8371]
- CR UK/NIHR in England/DoH for Scotland, Wales and Northern Ireland Experimental Cancer Medicine Centre
- BBSRC [BB/H019634/1]
- Overseas Research Students Award Scheme
- Biotechnology and Biological Sciences Research Council [BB/H019634/1] Funding Source: researchfish
- Cancer Research UK [11060, 15774] Funding Source: researchfish
- Medical Research Council [MR/J006742/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10140] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/H019634/1] Funding Source: Medline
- Cancer Research UK [C16736/A8371, C30122/A11527, C1519/A10331] Funding Source: Medline
- Medical Research Council [MR/J006742/1] Funding Source: Medline
Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironrnents, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22(+) B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of Fc gamma RI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.
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