Kumaresan Pappanaicken R, da Silva Thiago Aparecido, Kontoyiannis Dimitrios P
Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Department of Infectious Diseases, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
Front Immunol. 2018 Jan 8;8:1939. doi: 10.3389/fimmu.2017.01939. eCollection 2017.
Invasive fungal infections (IFIs) cause high rates of morbidity and mortality in immunocompromised patients. Pattern-recognition receptors present on the surfaces of innate immune cells recognize fungal pathogens and activate the first line of defense against fungal infection. The second line of defense is the adaptive immune system which involves mainly CD4 T cells, while CD8 T cells also play a role. CD8 T cell-based vaccines designed to prevent IFIs are currently being investigated in clinical trials, their use could play an especially important role in acquired immune deficiency syndrome patients. So far, none of the vaccines used to treat IFI have been approved by the FDA. Here, we review current and future antifungal immunotherapy strategies involving CD8 T cells. We highlight recent advances in the use of T cells engineered using a Sleeping Beauty vector to treat IFIs. Recent clinical trials using chimeric antigen receptor (CAR) T-cell therapy to treat patients with leukemia have shown very promising results. We hypothesized that CAR T cells could also be used to control IFI. Therefore, we designed a CAR that targets β-glucan, a sugar molecule found in most of the fungal cell walls, using the extracellular domain of Dectin-1, which binds to β-glucan. Mice treated with D-CAR T cells displayed reductions in hyphal growth of compared to the untreated group. Patients suffering from IFIs due to primary immunodeficiency, secondary immunodeficiency (e.g., HIV), or hematopoietic transplant patients may benefit from bioengineered CAR T cell therapy.
侵袭性真菌感染（IFI）在免疫功能低下的患者中导致高发病率和死亡率。先天免疫细胞表面存在的模式识别受体识别真菌病原体并激活针对真菌感染的第一道防线。第二道防线是适应性免疫系统，主要涉及CD4 T细胞，而CD8 T细胞也发挥作用。目前正在临床试验中研究旨在预防IFI的基于CD8 T细胞的疫苗，其使用在获得性免疫缺陷综合征患者中可能发挥特别重要的作用。到目前为止，用于治疗IFI的疫苗均未获得美国食品药品监督管理局（FDA）的批准。在此，我们综述涉及CD8 T细胞的当前和未来抗真菌免疫治疗策略。我们重点介绍了使用睡美人载体工程改造的T细胞治疗IFI的最新进展。最近使用嵌合抗原受体（CAR）T细胞疗法治疗白血病患者的临床试验显示出非常有前景的结果。我们假设CAR T细胞也可用于控制IFI。因此，我们设计了一种靶向β-葡聚糖的CAR，β-葡聚糖是一种存在于大多数真菌细胞壁中的糖分子，使用与β-葡聚糖结合的Dectin-1的细胞外结构域。与未治疗组相比，用D-CAR T细胞治疗的小鼠菌丝生长减少。因原发性免疫缺陷、继发性免疫缺陷（如HIV）或造血移植患者而患有IFI的患者可能受益于生物工程CAR T细胞疗法。
