IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells

Authors：Jiang, Zhiwu; Liao, Rui; Lv, Jiang; Li, Shanglin; Zheng, Diwei; Qin, Le; Wu, Di; Chen, Suimin; Long, Youguo; Wu, Qiting; Wang, Suna; Lin, Simiao; Huang, Xiaohan; Tang, Zhaoyang; Shi, Pengcheng; Zhou, Hongsheng; Liu, Qifa; Zhao, Ruocong; Li, Yangqiu; Jie, Yang; Wei, Wei; Lai, Peilong; Du, Xin; Cui, Shuzhong; Weinkove, Robert; Liu, Pentao; Pei, Duanqing; Yao, Yao^*; Li, Peng

Source：Leukemia, 2021, 35(5): 1380-1391.

DOI：10.1038/s41375-020-01085-1

• CYTOKINE RELEASE SYNDROME
• IN-VIVO
• INTERLEUKIN-6
• BLOCKADE
• EXPRESSION
• STRATEGIES
• EFFICACY
• MOUSE
• GP130

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.

• Institution
  广州医学院; 南方医科大学; 中国科学院; 广东省人民医院; 河北医科大学; 中国科学院研究生院; y