Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Sci Immunol. 2022 Jan 7;7(67):eabi6899. doi: 10.1126/sciimmunol.abi6899.
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.
有效地重新激活先前存在的肿瘤浸润淋巴细胞（TIL）而不引起严重毒性是一个挑战。白细胞介素 12（IL-12）可以强有力地激活淋巴细胞，但由于其半衰期短和剂量相关的毒性，其临床应用受到限制。在这项研究中，我们开发了一种肿瘤条件性 IL-12（前体 IL-12），它通过肿瘤表达的基质金属蛋白酶将 IL-12 与 IL-12 受体的选择性细胞外受体结合结构域掩蔽起来，而在被掩蔽后优先和持续地激活 TIL。与 IL-12-Fc 相比，系统递送前体 IL-12 显示出降低的毒性，但对已建立的肿瘤具有更好的控制。从机制上讲，前体 IL-12 诱导的抗肿瘤反应依赖于 TIL 和 IFNγ。此外，IL-12 与 CD8 而不是 CD4 T 细胞上的 IL-12R 的直接结合对于最大效力是必需的。当与免疫检查点阻断和靶向治疗联合使用时，前体 IL-12 提高了疗效。因此，我们的研究表明，前体 IL-12 可以使 TIL 恢复活力，然后与当前的治疗方式相结合，同时限制不良反应，用于治疗已建立的肿瘤。
