PDF(Pubmed)
Abstract：
Tumor-associated macrophages (TAMs) shape tumor immunity and therapeutic efficacy. However, it is poorly understood whether and how post-translational modifications (PTMs) intrinsically affect the phenotype and function of TAMs. Here, we reveal that peptidylarginine deiminase 4 (PAD4) exhibits the highest expression among common PTM enzymes in TAMs and negatively correlates with the clinical response to immune checkpoint blockade. Genetic and pharmacological inhibition of PAD4 in macrophages prevents tumor progression in tumor-bearing mouse models, accompanied by an increase in macrophage major histocompatibility complex (MHC) class II expression and T cell effector function. Mechanistically, PAD4 citrullinates STAT1 at arginine 121, thereby promoting the interaction between STAT1 and protein inhibitor of activated STAT1 (PIAS1), and the loss of PAD4 abolishes this interaction, ablating the inhibitory role of PIAS1 in the expression of MHC class II machinery in macrophages and enhancing T cell activation. Thus, the PAD4-STAT1-PIAS1 axis is an immune restriction mechanism in macrophages and may serve as a cancer immunotherapy target.
摘要：
肿瘤相关巨噬细胞(TAM)塑造肿瘤免疫和治疗功效。然而,对翻译后修饰（PTMs）是否以及如何内在地影响TAMs的表型和功能的了解甚少。我们发现,肽基精氨酸脱亚胺酶4(PAD4)在TAM中常见的PTM酶中表现出最高的表达,并且与免疫检查点阻断的临床应答呈负相关.巨噬细胞中PAD4的遗传和药理学抑制可防止荷瘤小鼠模型中的肿瘤进展，伴随着巨噬细胞主要组织相容性复合物（MHC）II类表达和T细胞效应子功能的增加。机械上,PAD4在精氨酸121处瓜氨酸STAT1，从而促进STAT1与活化STAT1蛋白抑制剂（PIAS1）之间的相互作用，PAD4的丢失消除了这种相互作用，消除PIAS1在巨噬细胞中MHCII类机制表达中的抑制作用并增强T细胞活化。因此，PAD4-STAT1-PIAS1轴是巨噬细胞中的一种免疫限制机制,可作为癌症免疫治疗的靶点.
