In:
Science Immunology, American Association for the Advancement of Science (AAAS), Vol. 7, No. 67 ( 2022-01-07)
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.
Type of Medium:
Online Resource
ISSN:
2470-9468
DOI:
10.1126/sciimmunol.abi6899
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2022
detail.hit.zdb_id:
2862556-0
