TY - JOUR
T1 - CTLA-4 limits anti-CD20-mediated tumor regression
AU - Ren, Zhenhua
AU - Guo, Jingya
AU - Liao, Jing
AU - Luan, Yan
AU - Liu, Zhida
AU - Sun, Zhichen
AU - Liu, Xiaojuan
AU - Liang, Yong
AU - Peng, Hua
AU - Fu, Yang Xin
N1 - Funding Information:
We are grateful to Dr. Mingzhao Zhu (Institute of Biophysics, CAS) for helpful suggestions and comments on the project. We thank Daryl Harmon (University of Texas Southwestern Medical Center, Dallas, Texas) for helpful editing and discussions. We thank Junjing Yu, Hui Su, and Qing Li (Institute of Biophysics, CAS) for technical assistance. This work was supported by the National Nature and Science Foundation of China grant (No. 81172814) to H. Peng, the National Science and Technology Major Project of China grant (no. 2012ZX10001006) to H. Peng, the National Nature Science Foundation of China grant (no. 81202328) to Y. Luan, and the Ministry of Science and Technology of China grant (No. 2011DFA31250; to Y.-X. Fu). This work was in part supported by the U.S. NIH through National Cancer Institute grants CA141975 to Y.-X. Fu. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.
AB - Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.
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U2 - 10.1158/1078-0432.CCR-16-0040
DO - 10.1158/1078-0432.CCR-16-0040
M3 - Article
C2 - 27354469
AN - SCOPUS:85010214313
SN - 1078-0432
VL - 23
SP - 193
EP - 203
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -