Tao Huimin, Lu Lin, Xia Yang, Dai Fu, Wang Yi, Bao Yangyi, Lundy Steven K, Ito Fumito, Pan Qin, Zhang Xiaolian, Zheng Fang, Shu Guoshun, Fang Bingmu, Jiang Jinhong, Xia Jianchuang, Huang Shiang, Li Qiao, Chang Alfred E
Department of Surgery, University of Michigan, , Ann Arbor, MI, USA; Hubei Province Stem Cell Research and Appling Center, Institute of Hematology, , Union Hospital, , Tongji Medical College, , Huazhong University of Science and Technology, Wuhan, China.
Eur J Immunol. 2015 Apr;45(4):999-1009. doi: 10.1002/eji.201444625. Epub 2015 Jan 21.
We have previously reported that adoptive transfer of tumor-draining lymph node (TDLN) B cells confers tumor regression in a spontaneous pulmonary metastasis mouse model of breast cancer. In this study, we identified IL-10-producing cells within these B cells, and found that IL-10 removal, either by using IL-10(-/-) TDLN B cells or by systemic neutralization of IL-10, significantly augmented the therapeutic efficacy of adoptively transferred TDLN B cells. Depletion of IL-10 in B-cell adoptive transfers significantly increased CTLs and B-cell activity of PBMCs and splenic cells in the recipient. Activated TDLN B cells express Fas ligand, which was further enhanced by coculture of these TDLN B cells with 4T1 tumor cells. Effector B cells killed tumor cells directly in vitro in an antigen specific and Fas ligand-dependent manner. Trafficking of TDLN B cells in vivo suggested that they were recruited to the tumor and lung as well as secondary lymphoid organs. These findings further define the biological function of antitumor effector B cells, which may offer alternative cellular therapies to cancer.
我们之前报道过，在乳腺癌自发性肺转移小鼠模型中，过继转移肿瘤引流淋巴结（TDLN）B细胞可使肿瘤消退。在本研究中，我们在这些B细胞中鉴定出产生白细胞介素10（IL-10）的细胞，并发现通过使用IL-10基因敲除的TDLN B细胞或通过全身性中和IL-10去除IL-10，可显著增强过继转移的TDLN B细胞的治疗效果。在B细胞过继转移中去除IL-10可显著增加受体中PBMC和脾细胞的细胞毒性T淋巴细胞（CTL）及B细胞活性。活化的TDLN B细胞表达Fas配体，这些TDLN B细胞与4T1肿瘤细胞共培养可进一步增强Fas配体的表达。效应B细胞在体外以抗原特异性和Fas配体依赖性方式直接杀伤肿瘤细胞。TDLN B细胞在体内的迁移表明它们被募集到肿瘤、肺以及二级淋巴器官。这些发现进一步明确了抗肿瘤效应B细胞的生物学功能，这可能为癌症提供替代性的细胞疗法。
