Science Immunology, 7 January, 2022, DOI：https://doi.org/10.1126/sciimmunol.abi6899
A tumor-specific pro-IL-12 activates preexisting cytotoxic T cells to control established tumors
Diyuan Xue, Benjamin Moon, Jing Liao, Jingya Guo, Zhuangzhi Zou, Yanfei Han, Shuaishuai Cao, Yang Wang, Yang-Xin Fu and Hua Peng
Abstract
It is a challenge to effectively reactivate preexisting tumor-infiltrating lymphocytes (TILs) without causing severe toxicity. Interleukin-12 (IL-12) can potently activate lymphocytes, but its clinical use is limited by its short half-life and dose-related toxicity. In this study, we developed a tumor-conditional IL-12 (pro-IL-12), which masked IL-12 with selective extracellular receptor–binding domains of the IL-12 receptor while preferentially and persistently activating TILs after being unmasked by matrix metalloproteinases expressed by tumors. Systemic delivery of pro-IL-12 demonstrated reduced toxicity but better control of established tumors compared with IL-12-Fc. Mechanistically, antitumor responses induced by pro-IL-12 were dependent on TILs and IFNγ. Furthermore, direct binding of IL-12 to IL-12R on CD8+, not CD4+, T cells was essential for maximal effectiveness. Pro-IL-12 improved the efficacy of both immune checkpoint blockade and targeted therapy when used in combination. Therefore, our study demonstrated that pro-IL-12 could rejuvenate TILs, which then combined with current treatment modalities while limiting adverse effects for treating established tumors.
文章链接：https://www.science.org/doi/10.1126/sciimmunol.abi6899
相关报道：http://www.ibp.cas.cn/kyjz/zxdt/202201/t20220107_6336897.html
附件下载：