Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.
Animal Resource Center, University of Chicago, Chicago, IL, USA.
Nat Biomed Eng. 2022 Jul;6(7):819-829. doi: 10.1038/s41551-022-00888-0. Epub 2022 May 9.
Immune-checkpoint inhibitors have shown modest efficacy against immunologically 'cold' tumours. Interleukin-12 (IL-12)-a cytokine that promotes the recruitment of immune cells into tumours as well as immune cell activation, also in cold tumours-can cause severe immune-related adverse events in patients. Here, by exploiting the preferential overexpression of proteases in tumours, we show that fusing a domain of the IL-12 receptor to IL-12 via a linker cleavable by tumour-associated proteases largely restricts the pro-inflammatory effects of IL-12 to tumour sites. In mouse models of subcutaneous adenocarcinoma and orthotopic melanoma, masked IL-12 delivered intravenously did not cause systemic IL-12 signalling and eliminated systemic immune-related adverse events, led to potent therapeutic effects via the remodelling of the immune-suppressive microenvironment, and rendered cold tumours responsive to immune-checkpoint inhibition. We also show that masked IL-12 is activated in tumour lysates from patients. Protease-sensitive masking of potent yet toxic cytokines may facilitate their clinical translation.
免疫检查点抑制剂对免疫“冷”肿瘤的疗效有限。白细胞介素-12（IL-12）是一种细胞因子，可促进免疫细胞浸润肿瘤并激活免疫细胞，即使在冷肿瘤中也有作用，但会在患者中引起严重的免疫相关不良反应。在这里，我们利用肿瘤中蛋白酶的优先过度表达，通过与肿瘤相关蛋白酶可切割的接头将 IL-12 受体的一个结构域融合到 IL-12 上，这在很大程度上限制了 IL-12 的促炎作用仅限于肿瘤部位。在皮下腺癌和原位黑色素瘤的小鼠模型中，静脉内给予掩蔽的 IL-12 不会引起全身 IL-12 信号转导，并消除全身免疫相关不良反应，通过重塑免疫抑制微环境产生强大的治疗效果，并使冷肿瘤对免疫检查点抑制敏感。我们还表明，掩蔽的 IL-12 在来自患者的肿瘤裂解物中被激活。有效的但毒性细胞因子的蛋白酶敏感掩蔽可能有助于其临床转化。
