Ren Zhenhua, Guo Jingya, Liao Jing, Luan Yan, Liu Zhida, Sun Zhichen, Liu Xiaojuan, Liang Yong, Peng Hua, Fu Yang-Xin
Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Clin Cancer Res. 2017 Jan 1;23(1):193-203. doi: 10.1158/1078-0432.CCR-16-0040. Epub 2016 Jun 27.
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.
在异种移植肿瘤模型中，抗CD20抗体（Ab）治疗对肿瘤生长的抑制作用是由抗体和补体依赖性细胞毒性介导的。此外，B细胞淋巴瘤的抗CD20治疗可导致肿瘤对进一步的抗体治疗产生内在和外在抗性。然而，在抗CD20介导的肿瘤控制中，与适应性免疫反应相关的抗性尚未得到充分研究，并且适应性免疫长期以来一直被低估。本研究的目的是探讨T细胞是否参与介导抗CD20治疗的效果以及哪些因素促成了与适应性免疫反应相关的抗性。
使用同基因小鼠B细胞淋巴瘤模型，我们研究了CD8 T细胞在抗CD20介导的肿瘤消退中的作用。此外，我们揭示了抗CD20如何引发肿瘤特异性T细胞反应。最后，我们研究了晚期B细胞淋巴瘤中与适应性免疫反应相关的抗性。
CD8 T细胞在抗CD20介导的肿瘤消退中起重要作用。机制上，抗CD20治疗促进了树突状细胞（DC）介导的交叉呈递。重要的是，巨噬细胞对于抗CD20治疗后肿瘤特异性CTL反应的增加也是必需的，其通过产生I型干扰素来激活DC功能。此外，在较大的淋巴瘤中，适应性抗性通过Treg细胞中的CTLA-4途径逐渐形成。进一步阻断CTLA-4可与抗CD20治疗在抗肿瘤活性中产生协同作用。
抗CD20的治疗功能取决于抗CD20通过巨噬细胞和DC引发的肿瘤特异性CD8 T细胞反应。阻断CTLA-4可与抗CD20协同作用，以克服晚期B细胞淋巴瘤中与适应性免疫反应相关的抗性。《临床癌症研究》；23(1)；193 - 203。©2016美国癌症研究协会。
