Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability 1 , 2 . In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance anti-tumour immunity. However, recombinant IL-18 previously did not demonstrate efficacy in clinical trials 3 . Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and mouse tumours and limits the anti-tumour activity of IL-18 in mice. Using directed evolution, we engineered a ‘decoy-resistant’ IL-18 (DR-18) that maintains signalling potential but is impervious to inhibition by IL-18BP. Unlike wild-type IL-18, DR-18 exerted potent anti-tumour effects in mouse tumour models by promoting the development of poly-functional effector CD8 + T cells, decreasing the prevalence of exhausted CD8 + T cells that express the transcriptional regulator of exhaustion TOX, and expanding the pool of stem-like TCF1 + precursor CD8 + T cells. DR-18 also enhanced the activity and maturation of natural killer cells to effectively treat anti-PD-1 resistant tumours that have lost surface expression of major histocompatibility complex class I molecules. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier. An engineered version of IL-18 that is resistant to binding by the soluble decoy receptor IL-18BP shows strong anti-tumour activity in mouse models of cancer.

中文翻译：

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IL-18BP 是分泌的免疫检查点和 IL-18 免疫治疗的屏障

细胞因子是第一个在晚期癌症患者中产生持久反应的现代免疫疗法，但它们的疗效有限，耐受性有限 1 , 2 。为了确定免疫治疗的替代细胞因子途径，我们发现白细胞介素 18 (IL-18) 途径的成分在肿瘤浸润淋巴细胞上被上调，这表明 IL-18 疗法可以增强抗肿瘤免疫。然而，重组 IL-18 以前并未在临床试验 3 中证明疗效。在这里，我们表明 IL-18BP 是一种高亲和力 IL-18 诱饵受体，在多种人和小鼠肿瘤中经常上调，并限制了 IL-18 在小鼠中的抗肿瘤活性。使用定向进化，我们设计了一种“抗诱饵”IL-18 (DR-18)，它保持了信号传导的潜力，但不受 IL-18BP 的抑制。与野生型 IL-18 不同，DR-18 通过促进多功能效应 CD8 + T 细胞的发育，降低表达耗尽 TOX，并扩大干细胞样 TCF1 + 前体 CD8 + T 细胞库。DR-18 还增强了自然杀伤细胞的活性和成熟度，以有效治疗已失去主要组织相容性复合物 I 类分子表面表达的抗 PD-1 抗性肿瘤。这些结果突出了 IL-18 通路在免疫治疗干预方面的潜力，并暗示 IL-18BP 作为主要的治疗屏障。对可溶性诱饵受体 IL-18BP 的结合具有抗性的 IL-18 工程化版本在小鼠癌症模型中显示出强大的抗肿瘤活性。