Deceleration of glycometabolism impedes IgG-producing B-cell-mediated tumor elimination by targeting SATB1
Deceleration of glycometabolism impedes IgG-producing B-cell-mediated tumor elimination by targeting SATB1
复制标题
糖代谢减慢会通过靶向 SATB1 阻碍产生 IgG 的 B 细胞介导的肿瘤消除。
DOI：
10.1111/imm.12998
复制
发表时间：
2019-01-01
期刊：
影响因子：
6.4
通讯作者：
Chu, Yiwei
中科院分区：
文献类型：
--
作者：
Liu, Jiajing;Li, Yifan;Chu, Yiwei
B淋巴细胞作为抗体产生者，以抗体依赖的细胞介导的细胞毒作用介导肿瘤细胞的破坏；然而，在肿瘤的发生过程中，其抗肿瘤功能似乎被削弱，其潜在的机制尚不清楚。在本研究中，我们发现了免疫球蛋白介导的抗肿瘤作用，但在各种肿瘤中产生免疫球蛋白的B细胞减少。考虑到潜在的机制，糖代谢是值得注意的。我们发现，肿瘤浸润性B细胞是葡萄糖饥饿的，并伴有糖代谢减速。抑制糖代谢和通过肿瘤细胞剥夺葡萄糖，或无糖治疗，都会减少B细胞分化为产生免疫球蛋白的细胞。在这个过程中，B细胞中特异的富含AT的序列结合蛋白-1(SATB1)被显著沉默。通过抑制糖代谢或RNA干扰来下调SATB1，减少信号转导和转录激活因子6(STAT6)与生殖系C基因启动子的结合，从而导致更少的B细胞产生免疫球蛋白。我们的发现首次证明，肿瘤发生过程中糖代谢的抑制抑制了B细胞向产生免疫球蛋白的细胞的分化，改变糖代谢在提高B细胞的抗肿瘤作用方面可能是有希望的。
B lymphocytes, known as antibody producers, mediate tumor cell destruction in the manner of antibody-dependent cell-mediated cytotoxicity; however, their anti-tumor function seems to be weakened during tumorigenesis, while the underlying mechanisms remain unclear. In this study, we found that IgG mediated anti-tumor effects, but IgG-producing B cells decreased in various tumors. Considering the underlying mechanism, glycometabolism was noteworthy. We found that tumor-infiltrating B cells were glucose-starved and accompanied by a deceleration of glycometabolism. Both inhibition of glycometabolism and deprivation of glucose through tumor cells, or glucose-free treatment, reduced the differentiation of B cells into IgG-producing cells. In this process, special AT-rich sequence-binding protein-1 (SATB1) was significantly silenced in B cells. Down-regulating SATB1 by inhibiting glycometabolism or RNA interference reduced the binding of signal transducer and activator of transcription 6 (STAT6) to the promoter of germline C gene, subsequently resulting in fewer B cells producing IgG. Our findings provide the first evidence that glycometabolic inhibition by tumorigenesis suppresses differentiation of B cells into IgG-producing cells, and altering glycometabolism may be promising in improving the anti-tumor effect of B cells.