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IL-18BP是IL-18免疫疗法的障碍
2020-06-28 14:12

美国耶鲁大学Aaron M. Ring研究团队发现,IL-18BP是分泌的免疫检查点以及IL-18免疫疗法的障碍。该研究于2020年6月24日在线发表于《自然》。

为了确定用于免疫疗法的其他细胞因子途径,研究人员发现白细胞介素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治疗可以增强抗肿瘤免疫力。但是,重组IL-18以前在临床试验中未显示出疗效。研究人员发现了IL-18BP,这是一种高亲和力的IL-18诱饵受体,经常在多种人类和小鼠肿瘤中上调,并限制了IL-18在小鼠中的抗肿瘤活性。
 
通过定向进化,研究人员设计了一种“抗诱饵的” IL-18(DR-18),它可以维持信号转导潜能,但不能被IL-18BP抑制。与野生型IL-18不同,DR-18通过促进多功能效应子CD8+T细胞的发育,降低耗竭CD8+T细胞的出现,并且扩大干细胞样TCF1+前体CD8+T细胞库,从而在小鼠肿瘤模型中发挥强大的抗肿瘤作用。DR-18还增强了自然杀伤细胞的活性和成熟度,从而可以有效地治疗抗PD-1耐药性肿瘤。
 
这些结果突出了IL-18途径在免疫治疗干预中的潜力,并暗示IL-18BP是主要的治疗障碍。
 
据了解,细胞因子是在晚期癌症患者中产生持久应答的首个现代免疫疗法,但它们仅具有一定的疗效和有限的耐受性。
 
附:英文原文

Title: IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy

Author: Ting Zhou, William Damsky, Orr-El Weizman, Meaghan K. McGeary, K. Patricia Hartmann, Connor E. Rosen, Suzanne Fischer, Ruaidhri Jackson, Richard A. Flavell, Jun Wang, Miguel F. Sanmamed, Marcus W. Bosenberg, Aaron M. Ring

Issue&Volume: 2020-06-24

Abstract: Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability1,2. 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 trials3. 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.

DOI: 10.1038/s41586-020-2422-6

Source: https://www.nature.com/articles/s41586-020-2422-6

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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