Department of Medicine, Division of Hematology and Oncology, Case Western Reserve University, Cleveland, OH, United States.
Medical Affairs, Partner Therapeutics, Inc., Lexington, MA, United States.
Front Immunol. 2023 Jan 5;13:1069444. doi: 10.3389/fimmu.2022.1069444. eCollection 2022.
Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.
We reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.
We discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.
We identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.
内源性粒细胞-巨噬细胞集落刺激因子（GM-CSF）因其能够支持造血细胞分化为多种类型的髓样细胞而被识别，现在已知它支持单核吞噬细胞（包括单核细胞、巨噬细胞和树突状细胞）的成熟并维持其代谢能力。这些细胞可以感知和攻击潜在的病原体，向适应性免疫细胞呈递抗原，并招募其他免疫细胞。重组人（rhu）GM-CSF（例如，沙格司亭[糖基化，酵母来源的 rhu GM-CSF]）具有免疫调节特性，可恢复因内源性 GM-CSF 缺乏或不足而功能失调的单核吞噬细胞的正常功能。
我们回顾了 GM-CSF 的新兴生物学和细胞作用。内源性 GM-CSF 缺乏或不足引起的临床疾病领域的专家检查了 GM-CSF 在单核吞噬细胞疾病中的作用，包括自身免疫性肺泡蛋白沉积症（aPAP）、多种感染（包括 COVID-19）、伤口愈合和抗癌症免疫检查点抑制剂治疗。
我们讨论了 GM-CSF 生物学的新兴数据，包括对线粒体功能和细胞代谢的积极影响、吞噬作用和胞吐作用的增强以及免疫细胞调节。我们进一步探讨了给予外源性 rhu GM-CSF 如何控制或治疗由 GM-CSF 缺乏或不足引起或加重的单核吞噬细胞功能障碍疾病。我们讨论了 rhu GM-CSF 如何增强免疫检查点抑制剂免疫治疗的抗癌作用以及改善免疫相关不良事件。
我们确定了研究差距、机会以及 rhu GM-CSF 通过支持和恢复单核吞噬细胞的代谢能力和功能可以产生显著治疗效果的概念。rhu GM-CSF（例如，沙格司亭）可能会改善 GM-CSF 缺乏或不足的多种疾病，并解决高度未满足的医疗需求。
