Myeloma-derived IL-32γ induced PD-L1 expression in macrophages facilitates immune escape via the PFKFB3-JAK1 axis.
Myeloma-derived IL-32γ induced PD-L1 expression in macrophages facilitates immune escape via the PFKFB3-JAK1 axis.
复制标题
骨髓瘤衍生的 IL-32γ 诱导巨噬细胞中的 PD-L1 表达通过 PFKFB3-JAK1 轴促进免疫逃逸
DOI：
10.1080/2162402x.2022.2057837
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发表时间：
2022
期刊：
影响因子：
7.2
通讯作者：
Cai Z
中科院分区：
文献类型：
--
作者：
Liu Y;Yan H;Gu H;Zhang E;He J;Cao W;Qu J;Xu R;Cao L;He D;Zhang J;Hou Y;Cai Z
多发性骨髓瘤（MM）的特征在于单克隆浆细胞在骨髓（BM）内的积聚。巨噬细胞是骨髓瘤BM微环境的丰富组成部分，支持恶性细胞的生存，并通过抑制免疫反应促进骨髓瘤的发育和进展。在我们之前的研究中，我们发现MM患者过度表达促炎细胞因子白细胞介素-32（IL-32）。本研究旨在探讨IL-32在骨髓瘤进展中的作用以及IL-32对巨噬细胞功能的作用机制。我们发现IL-32的表达与骨髓瘤患者的疾病分期相关。含有IL-32γ的MM衍生外泌体促进巨噬细胞表达程序性死亡配体1（PD-L1），从而促进免疫逃避。从机制上讲，骨髓瘤分泌的IL-32γ通过蛋白酶3（PR 3）发挥作用，增强6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3（PFKFB 3）依赖性糖酵解和随后的PD-L1表达。此外，PFKFB 3-Janus激酶1（JAK 1）轴可能有助于巨噬细胞表达PD-L1。综上所述，我们得出结论，IL-32是骨髓瘤进展中的关键介质，靶向IL-32信号传导可能被用作治疗骨髓瘤的潜在策略。
Multiple myeloma (MM) is characterized by an accumulation of monoclonal plasma cells within the bone marrow (BM). Macrophages are an abundant component of myeloma BM microenvironment and support survival of the malignant cells and foster myeloma development and progression by suppression of the immune response. In our previous study, we found that MM patients overexpress pro-inflammatory cytokine interleukin-32 (IL-32). The present study aimed to investigate the role of IL-32 in myeloma progression and mechanisms of IL-32 on macrophages functions. We discovered that the expression of IL-32 was associated with the disease stage in myeloma patients. MM-derived exosomes containing IL-32γ promoted the expression of programmed death-ligand 1(PD-L1) by macrophages, thus promoting immune evasion. Mechanistically, myeloma-secreted IL-32γ acted via proteinase 3 (PR3) to enhance 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) dependent glycolysis and subsequent PD-L1 expression. Moreover, the PFKFB3-Janus kinase 1 (JAK1) axis might contribute to the expression of PD-L1 by macrophages. To sum up, we concluded that IL-32 was a critical mediator in myeloma progression, and targeting IL-32 signaling might be used as a potential strategy for treating myeloma.