Mizuno Nobuyo, Boehm Dylan, Jimenez-Perez Kevin, Abraham Jinu, Springgay Laura, Rose Ian, DeFilippis Victor R
Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.
bioRxiv. 2025 Feb 27:2025.02.21.639458. doi: 10.1101/2025.02.21.639458.
Pharmacologic activation of the innate immune response is being actively being pursued for numerous clinical purposes including enhancement of vaccine potency and potentiation of anti-cancer immunotherapy. Pattern recognition receptors (PRRs) represent especially useful targets for these efforts as their engagement by agonists can trigger signaling pathways that associate with phenotypes desirable for specific immune outcomes. Stimulator of interferon genes (STING) is an ER-resident PRR reactive to cyclic dinucleotides such as those synthesized endogenously in response to cytosolic dsDNA. STING activation leads to transient generation of type I interferon (IFN-I) and proinflammatory responses that augment immunologically relevant effects including antiviral responses, antigen presentation, immune cell trafficking, and immunogenic cell death. In recent years engineered cyclic dinucleotides and small molecules have been discovered that induce STING and safely confer clinically useful outcomes in animal models such as adjuvanticity of anti-microbial vaccines and tumor clearance. Unfortunately, clinical trials examining the efficacy of STING agonists have thus far failed to satisfactorily recapitulate these positive outcomes and this has prevented their translational advancement. A likely relevant yet perplexingly under investigated aspect of pharmacologic STING activation is the diversity of molecular and immune responses that associate with chemical properties of the agonist. Based on this, a comparative survey of these was undertaken using unrelated STING-activating molecules to characterize the molecular, innate, cellular, and immune outcomes they elicit. This was done to inform and direct future studies aimed at designing and selecting agonists appropriate for desired clinical goals. This revealed demonstrable differences between the agonists in potency, transcriptomes, cytokine secretion profiles, immune cell trafficking, and antigen-directed humoral and cell mediated immune responses. As such, this work illustrates that phenotypes deriving from activation of a protein target can be linked to chemical properties of the engaging agonist and thus heightened scrutiny is necessary when selecting molecules to generate specific effects.
为了实现包括增强疫苗效力和强化抗癌免疫疗法在内的众多临床目标，人们正在积极探索对先天免疫反应进行药理学激活。模式识别受体（PRR）是这些努力中特别有用的靶点，因为激动剂与它们的结合可以触发与特定免疫结果所需表型相关的信号通路。干扰素基因刺激物（STING）是一种驻留在内质网的PRR，对环状二核苷酸有反应，比如那些在细胞溶质双链DNA刺激下内源性合成的环状二核苷酸。STING激活会导致I型干扰素（IFN-I）的短暂产生和促炎反应，从而增强包括抗病毒反应、抗原呈递、免疫细胞运输和免疫原性细胞死亡在内的免疫相关效应。近年来，人们发现了工程化环状二核苷酸和小分子，它们能诱导STING，并在动物模型中安全地产生临床上有用的结果，如抗菌疫苗的佐剂作用和肿瘤清除。不幸的是，迄今为止，检验STING激动剂疗效的临床试验未能令人满意地重现这些积极结果，这阻碍了它们向临床转化。药理学STING激活一个可能相关但却令人困惑地未得到充分研究的方面是，与激动剂化学性质相关的分子和免疫反应的多样性。基于此，我们使用不相关的STING激活分子对这些方面进行了比较研究，以表征它们引发的分子、先天、细胞和免疫结果。这样做是为了为未来旨在设计和选择适合预期临床目标的激动剂的研究提供信息并加以指导。这揭示了激动剂在效力、转录组、细胞因子分泌谱、免疫细胞运输以及抗原导向的体液和细胞介导免疫反应方面存在明显差异。因此，这项工作表明，源自蛋白质靶点激活的表型可以与结合激动剂的化学性质相关联，因此在选择分子以产生特定效果时需要更严格的审查。
