It is a challenge to invigorate tumor-infiltrating lymphocytes without causing immune-related adverse events, which also stands as a primary factor contributing to resistance against cancer immunotherapies. Interleukin (IL)-15 can potently promote expansion and activation of T cells, but its clinical use has been limited by dose-limiting toxicities. In this study, we develop a tumor-conditional IL-15 (pro-IL-15), which masks IL-15 with steric hindrance caused by Fc fragment and IL-15Rα-sushi domain. Upon reaching the tumor site, it can be cleaved by tumor-associated proteases to release an IL-15 superagonist, resulting in potent antitumor activities. Systemic delivery of pro-IL-15 demonstrates significantly reduced toxicity but uncompromised antitumor efficacy. Pro-IL-15 can yield better effectors and vitalize terminally exhausted CD8+ T cells to overcome checkpoint blockade resistance. Moreover, pro-IL-15 promotes chemotaxis and activation of adoptive T cells, leading to eradication of advanced solid tumors and durable cures. Furthermore, pro-IL-15 shows promise for synergizing with other immunotherapies like IL-12 and oncolytic virus by improving the CD8/Treg ratio and interferon-γ levels, resulting in substantial regression of both local and metastatic cold tumors. Collectively, our results suggest that pro-IL-15 represents a compelling strategy for overcoming resistance to current immunotherapies while avoiding toxicities.

中文翻译：

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肿瘤条件性 IL-15 与免疫疗法安全协同作用，以增强抗肿瘤免疫反应


在不引起免疫相关不良事件的情况下激活肿瘤浸润淋巴细胞是一项挑战，这也是导致对癌症免疫疗法耐药的主要因素。白细胞介素 （IL）-15 可以有效促进 T 细胞的扩增和活化，但其临床应用受到剂量限制性毒性的限制。在这项研究中，我们开发了一种肿瘤条件性 IL-15 （pro-IL-15），它掩盖了由 Fc 片段和 IL-15Rα-sushi 结构域引起的空间位阻的 IL-15。到达肿瘤部位后，可被肿瘤相关蛋白酶裂解，释放 IL-15 超激动剂，从而产生有效的抗肿瘤活性。pro-IL-15 的全身递送显示出毒性显著降低，但抗肿瘤疗效不受影响。Pro-IL-15 可以产生更好的效应子并激活终末耗竭的 CD8+ T 细胞以克服检查点阻断耐药。此外，pro-IL-15 促进过继性 T 细胞的趋化性和活化，从而根除晚期实体瘤和持久治愈。此外，pro-IL-15 有望通过改善 CD8/Treg 比率和干扰素-γ水平，与 IL-12 和溶瘤病毒等其他免疫疗法协同作用，导致局部和转移性冷肿瘤的实质性消退。总的来说，我们的结果表明 pro-IL-15 代表了一种令人信服的策略，可以克服对当前免疫疗法的耐药性，同时避免毒性。