PDF(Pubmed)
Abstract：
Opportunistic fungal infections have high mortality in patients with severe immune dysfunction. Growing evidence suggests that the immune environment of invasive fungal infections and cancers share common features of immune cell exhaustion through activation of immune checkpoint pathways. This observation gave rise to several preclinical studies and clinical case reports describing blockade of the Programmed Cell Death Protein 1 and Cytotoxic T-Lymphocyte Antigen 4 immune checkpoint pathways as an adjunct immune enhancement strategy to treat opportunistic fungal infections. The first part of this review summarizes the emerging evidence for contributions of checkpoint pathways to the immunopathology of fungal sepsis, opportunistic mold infections, and dimorphic fungal infections. We then review the potential merits of immune checkpoint inhibitors (ICIs) as an antifungal immunotherapy, including the incomplete knowledge of the mechanisms involved in both immuno-protective effects and toxicities. In the second part of this review, we discuss the limitations of the current evidence and the many unknowns about ICIs as an antifungal immune enhancement strategy. Based on these gaps of knowledge and lessons learned from cancer immunology studies, we outline a research agenda to determine a \"sweet spot\" for ICIs in medical mycology. We specifically discuss the importance of more nuanced animal models, the need to study ICI-based combination therapy, potential ICI resistance, the role of the immune microenvironment, and the impact of ICIs given as part of oncological therapies on the natural immunity to various pathogenic fungi.
摘要：
机会性真菌感染在严重免疫功能障碍患者中具有高死亡率。越来越多的证据表明，侵袭性真菌感染和癌症的免疫环境通过激活免疫检查点途径具有免疫细胞耗竭的共同特征。这一观察结果引起了一些临床前研究和临床病例报告，描述了对程序性细胞死亡蛋白1和细胞毒性T淋巴细胞抗原4免疫检查点途径的阻断，作为治疗机会性真菌感染的辅助免疫增强策略。本综述的第一部分总结了检查点途径对真菌性败血症免疫病理学的贡献的新证据。机会性霉菌感染，和双态真菌感染。然后，我们回顾了免疫检查点抑制剂（ICIs）作为抗真菌免疫疗法的潜在优点。包括对免疫保护作用和毒性的机制的不完全了解。在本文的第二部分,我们讨论了目前证据的局限性以及ICIs作为抗真菌免疫增强策略的许多未知因素.基于这些知识的差距和从癌症免疫学研究中吸取的教训，我们概述了一个研究议程，以确定医学真菌学中ICI的“最佳点”。我们特别讨论了更细致的动物模型的重要性，需要研究基于ICI的联合治疗，潜在的ICI抗性，免疫微环境的作用，以及作为肿瘤疗法一部分的ICIs对各种病原真菌的天然免疫的影响。
