IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy
IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy
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DOI：
10.1038/s41586-020-2422-6
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发表时间：
2020-07-23
期刊：
影响因子：
64.8
通讯作者：
Ring, Aaron M.
中科院分区：
文献类型：
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作者：
Zhou, Ting;Damsky, William;Ring, Aaron M.
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）途径的组分在肿瘤浸润淋巴细胞上上调，表明IL-18治疗可以增强抗肿瘤免疫力。然而，重组IL-18以前在临床试验中没有表现出疗效（3）。在这里，我们表明，IL-18 BP，一种高亲和力的IL-18诱饵受体，在不同的人类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“诱饵抗性”IL-18（DR-18），其保持信号传导潜力，但不受IL-18 BP的抑制。与野生型IL-18不同，DR-18通过促进多功能效应CD 8（+）T细胞的发育，降低表达耗竭TOX转录调节因子的耗竭CD 8（+）T细胞的患病率，并扩大干细胞样TCF 1（+）前体CD 8（+）T细胞库，在小鼠肿瘤模型中发挥了有效的抗肿瘤作用。DR-18还增强了自然杀伤细胞的活性和成熟，以有效治疗失去主要组织相容性复合物I类分子表面表达的抗PD-1耐药肿瘤。这些结果突出了IL-18途径用于免疫干预的潜力，并暗示IL-18 BP是主要的治疗屏障。
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.