期刊
LEUKEMIA
卷 35, 期 5, 页码 1380-1391出版社
SPRINGERNATURE
DOI: 10.1038/s41375-020-01085-1
关键词
-
资金
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB19030205, XDA1205030]
- National Natural Science Foundation of China (NSFC) [81773301, 81700156, 8187012, 81873847]
- Youth Innovation Promotion Association of the Chinese Academy of Sciences [2020351]
- Guangdong Special Support Program [2017TX04R102]
- Frontier and key technology innovation special grant from the Department of Science and Technology of Guangdong province [2015B020227003]
- Natural Science Fund of Guangdong Province-Doctoral Foundation [2017A030310381]
- Guangdong Laboratory of Regenerative Medicine and Health-Guangzhou Frontier Exploration Project [2018GZR110105003]
- Science and Technology Planning Project of Guangdong Province, China [2017B030314056]
- Science and Technology Program of Guangzhou, China [202002020083]
- Guangzhou Medical University High-level University Construction Research Startup Fund [B195002004013]
CAR-T cell therapies have shown high clinical response rates in B cell malignancies, with potential for solid tumor treatment. Modulating IL-6 trans-signaling through GP130/STAT3 pathway enhances CAR-T cell expansion and antitumor activity, while GP130 expression in CAR-T cells improves antitumor efficacy without systemic IL-6 trans-signaling, indicating the potential for therapeutic applications.
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.
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