CTLA-4 Limits Anti-CD20-Mediated Tumor Regression

The inhibition of tumor growth by anti-CD20 antibody (Ab) treatment is mediated by Ab- and complement-dependent cytotoxicity in xenograft tumor models. In addition, anti-CD20 therapy for B-cell lymphoma can result in intrinsic and extrinsic tumor resistance to further Ab treatment. However, adaptive...

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Bibliographic Details
Published in:Clinical cancer research 2017-01, Vol.23 (1), p.193-203
Main Authors: Ren, Zhenhua, Guo, Jingya, Liao, Jing, Luan, Yan, Liu, Zhida, Sun, Zhichen, Liu, Xiaojuan, Liang, Yong, Peng, Hua, Fu, Yang-Xin
Format: Article
Language:English
Subjects:
Adaptive control
Adaptive immunity
Animal models
Anticancer properties
Antigen presentation
B-cell lymphoma
Cancer
CD20 antigen
CD8 antigen
CTLA-4 protein
Cytotoxicity
Dendritic cells
Experimental design
Immune response
Immune system
Immunity
Interferon
Lymphocytes
Lymphocytes B
Lymphocytes T
Lymphoma
Macrophages
Regression
Synergism
T cell receptors
Therapy
Toxicity
Xenografts
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Summary:The inhibition of tumor growth by anti-CD20 antibody (Ab) treatment is mediated by Ab- and complement-dependent cytotoxicity in xenograft tumor models. In addition, anti-CD20 therapy for B-cell lymphoma can result in intrinsic and extrinsic tumor resistance to further Ab treatment. However, adaptive immune response-related resistance has not been well studied in anti-CD20-mediated tumor control, and adaptive immunity has long been underestimated. The purpose of this study was to explore whether T cells are involved in mediating the effects of anti-CD20 therapy and what factors contribute to adaptive immune response-related resistance. Using a syngeneic mouse B-cell lymphoma model, we investigated the role of CD8 T cells in anti-CD20-mediated tumor regression. Furthermore, we revealed how the tumor-specific T-cell response was initiated by anti-CD20. Finally, we studied adaptive immune response-related resistance in advanced B-cell lymphoma. CD8 T cells played an essential role in anti-CD20-mediated tumor regression. Mechanistically, anti-CD20 therapy promoted dendritic cell (DC)-mediated cross-presentation. Importantly, macrophages were also necessary for the increase in the tumor-specific CTL response after anti-CD20 treatment, via the production of type I IFN to activate DC function. Furthermore, adaptive resistance is gradually developed through the CTLA-4 pathway in Treg cells in larger lymphomas. Further blockade of CTLA-4 can synergize with anti-CD20 treatment in antitumor activities. The therapeutic function of anti-CD20 depends on tumor-specific CD8 T-cell responses initiated by anti-CD20 through macrophages and DCs. CTLA-4 blockade can synergize with anti-CD20 to overcome adaptive immune response-related resistance in advanced B-cell lymphoma. Clin Cancer Res; 23(1); 193-203. ©2016 AACR.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-16-0040