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 - 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 -