IL-18: throwing off the shackles to boost anti-tumor immunity.
IL-18: throwing off the shackles to boost anti-tumor immunity.
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DOI：
10.1038/s41422-020-00396-3
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发表时间：
2020-10
期刊：
影响因子：
44.1
通讯作者：
Kuchroo VK
中科院分区：
文献类型：
--
作者：
Dixon KO;Kuchroo VK
细胞因子是在细胞信号传导和通讯中重要的可溶性分子，具有协调自身免疫、感染和癌症中的免疫应答的能力。干扰素强效杀肿瘤活性的发现为临床前模型中几种炎性细胞因子（包括IFN-α 1和IL-2，2）的深入临床研究铺平了道路，细胞因子治疗历来是癌症的重要治疗方式。虽然这些细胞因子的使用是癌症免疫治疗的一个重要里程碑，但作为单一疗法，它们尚未实现临床前模型中所见的疗效承诺。除了广泛的毒性外，低应答率在很大程度上降低了这些治疗剂的使用，而有利于免疫检查点抑制剂，包括抗CTLA-4和抗PD-1，这些药物在许多传统抗肿瘤治疗难治的患者中显示出深刻的临床益处。然而，只有约13%的患者对这些疗法有反应，3尽管在开发“二线”免疫疗法方面做出了重大努力，但除了现有策略外，还没有显著的附加临床益处。在这种情况下，人们重新关注增强炎性细胞因子与现有免疫调节剂（包括抗PD-1）组合的抗肿瘤作用。为了规避细胞因子免疫疗法的早期警告，例如多效性和低应答率，细胞因子现在也被工程化以产生维持其抗癌功效或定制其受体结合亲和力的“超级因子”。这通过具有增强的对IL-2 R β的亲和力和增加的效应T细胞功能的工程化IL-2样分子最好地例证。在《自然》杂志上发表的一项新研究中，作者试图利用现有的单细胞肿瘤浸润淋巴细胞（TIL）数据集探索肿瘤微环境（TME）中的新型细胞因子回路。6使用这种方法，他们发现IL 18 R1（编码IL-18 R α）和IL 18 RAP（编码IL-18 R β）的转录本在活化和功能失调的CD 8 + TIL中富集。尽管IL-18受体的表达谱很有希望，但之前已在II期临床试验中探索了IL-18，该临床试验由于临床疗效低而提前终止，未能重现在重组IL-18的临床前模型中观察到的强抗肿瘤免疫力。IL-18是细胞因子IL-1家族的成员，并且与IL-1β类似，是一种有效的炎性细胞因子。因此，两者都被严格调控并合成为前体，其在允许条件下被切割并释放为成熟的IL-1β和IL-18。在分泌后，这些细胞因子分别由诱饵受体IL-1 Ra和IL-18 BP进一步调节。IL-18 BP对IL-18的亲和力比IL-18 R α大约10，000倍，因此作者假设IL-18 BP可能抑制TME中IL-18的活性。作者发现，IL-18 BP的水平在人类和小鼠肿瘤中以IFN-γ依赖性方式升高。有趣的是，IL-27（驱动CD 8 TIL上共抑制模块表达的关键细胞因子）7也是IL-18 BP的有效诱导剂。因此，除了直接调节CD 8 + T细胞上表面抑制性受体的诱导外，IL-27还通过其对骨髓细胞的作用促进TME中的CD 8 + T细胞功能障碍，通过诱导许多细胞表面和可溶性抑制剂（包括IL-18 BP）促进负反馈回路。为了克服IL-18 BP的抑制作用，作者进行了IL-18变体的酵母展示筛选，以鉴定可结合IL-18 R α但不结合IL-18 BP的突变体。这个“诱饵...
Cytokines are soluble molecules important in cell signaling and communication, with the ability to orchestrate the immune response in autoimmunity, infection and cancer. The discovery of the potent tumoricidal activity of interferons paved the way for intense clinical investigation of several inflammatory cytokines in preclinical models, including IFN-α 1 and IL-2, 2 with cytokine therapy historically being an important treatment modality for cancer. While the use of these cytokines was a significant milestone in cancer immunotherapy, as a monotherapy they have not fulfilled the promise of efficacy seen in preclinical models. In addition to a wide range of toxicities, the low response rate has largely relegated the use of these therapeutics in favor of immune checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1, which have shown profound clinical benefits in a number of patients that were otherwise refractory to conventional anti-tumor therapies. However, only~ 13% of patients respond to these therapies, 3 and despite a major effort to develop “second line” immunotherapies, there has yet to be significant additive clinical benefit beyond existing strategies. In this context, there is a renewed interest in potentiating the anti-tumor effect of inflammatory cytokines in combination with existing immunomodulatory agents, including anti-PD-1. 4 To circumvent the earlier caveats with cytokine immunotherapy, such as pleiotrophism and low response rate, cytokines are now also being engineered to generate “superkines” sustaining their anti-cancer efficacy or tailoring their receptor-binding affinity. This is best exemplified by engineered IL-2-like molecules with augmented affinity for IL-2Rβ and increased effector T cell function. 5 In a new study published in Nature, the authors sought to explore novel cytokine circuits within the tumor microenvironment (TME) leveraging existing single-cell tumor-infiltrating lymphocyte (TIL) datasets. 6 Using this approach, they found that transcripts of IL18R1 (encoding IL-18Rα) and IL18RAP (encoding IL-18Rβ) were enriched in activated and dysfunctional CD8+ TILs. Despite the promising expression profile of the receptor, IL-18 had previously been explored in a phase II clinical trial which was prematurely terminated due to low clinical efficacy, failing to recapitulate the strong anti-tumor immunity seen in preclinical models with recombinant IL-18. IL-18 is a member of the IL-1 family of cytokines, and analogous to IL-1β is a potent inflammatory cytokine. As such, both are tightly regulated and synthesized as precursors, which, in permissive conditions, are cleaved and released as mature IL-1β and IL-18. Upon secretion these cytokines are further regulated by decoy receptors IL-1Ra and IL-18BP, respectively. The affinity ofIL-18BP for IL-18 is~ 10,000 times greater than that of IL-18Rα, leading the authors to hypothesize that IL-18BP might be inhibiting the activity of IL-18 in the TME. The authors found that levels of IL-18BP were elevated in both human and murine tumors in an IFN-γ-dependent manner. Interestingly, IL-27, a key cytokine driving expression of the co-inhibitory module on CD8 TILs, 7 is also a potent inducer of IL-18BP. Therefore, in addition to directly regulating the induction of surface inhibitory receptors on CD8+ T cells, IL-27 contributes to CD8+ T cell dysfunction in the TME through its action on myeloid cells, promoting a negative feedback loop through induction of a number of cell surface and soluble inhibitors, including IL-18BP. To overcome the inhibitory effect of IL-18BP, the authors performed a yeast display screening of IL-18 variants to identity mutants which could bind the IL-18Rα, but not IL-18BP. This “decoy …
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影响因子：
45.3
作者：
FYFE, G;FISHER, RI;LOUIE, AC
通讯作者：
LOUIE, AC
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15.3
作者：
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64.8
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Schietinger A
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64.8
作者：
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64.8
作者：
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Garcia, K. Christopher