IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells
IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells
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IL-6 反式信号传导促进 CAR T 细胞的扩增和抗肿瘤活性。
DOI：
10.1038/s41375-020-01085-1
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发表时间：
2020-11-09
期刊：
影响因子：
11.4
通讯作者：
Li, Peng
中科院分区：
文献类型：
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作者：
Jiang, Zhiwu;Liao, Rui;Li, Peng
嵌合抗原受体（CAR） T细胞疗法在B细胞恶性肿瘤中具有很高的临床反应率，并且正在研究用于治疗实体肿瘤。虽然高系统性白细胞介素- (IL-) 6水平与临床细胞因子释放综合征（CRS）相关，但IL-6反式信号在CAR - t细胞中的作用尚未报道。我们生成了组成性表达高IL-6 （HIL-6）的CAR - T细胞，这是一种激活反式信号通路的设计细胞因子。在体外和异种移植模型中，表达hil -6的CAR - t细胞表现出增强的增殖和抗肿瘤功效。然而，HIL-6 CAR - T细胞引起严重的移植物抗宿主病（GVHD）。转录组学分析显示，HIL-6刺激CAR - T细胞上调了与T细胞迁移、早期记忆分化和IL-6/GP130/STAT3信号传导相关的基因。由于IL-6反式信号通过表面GP130起作用，我们产生了表达GP130组成活性形式的CAR - T细胞，并发现这些细胞在b细胞白血病和实体瘤的临床前模型中保留了改善的抗肿瘤活性，没有GVHD的迹象。综上所述，这些结果表明，IL-6反式信号可以通过GP130/STAT3途径增强CAR - T细胞的增殖和抗肿瘤活性，并且表明在CAR - T细胞中表达GP130可以在没有全身IL-6反式信号的情况下提高抗肿瘤效果。
Chimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.