Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia
Soluble PD-1 ligands regulate T-cell function in Waldenstrom macroglobulinemia
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DOI：
10.1182/bloodadvances.2018021113
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发表时间：
2018-08-14
期刊：
影响因子：
7.5
通讯作者：
Ansell, Stephen M.
中科院分区：
文献类型：
--
作者：
Jalali, Shahrzad;Price-Troska, Tammy;Ansell, Stephen M.
虽然免疫检查点分子调节某些癌症的进展，但它们在Waldenstrom巨球蛋白血症（WM）（一种不可治愈的低度B细胞淋巴瘤）恶性发展中的意义仍然未知。最近，骨髓（BM）微环境中的细胞因子被证明有助于WM的病理生物学。在这里，我们研究了细胞因子，包括白细胞介素-6（IL-6）和IL-21对免疫调节的影响，特别是对程序性死亡-1（PD-1）及其配体PD-L1和PD-L2的影响。我们发现IL-21、干扰素γ和IL-6显著诱导WM细胞系中的PD-L1和PD-L2基因表达。在患者的BM细胞中也检测到PD-L1和PD-L2信使RNA增加。患者的非恶性BM细胞，包括T细胞和单核细胞，显示PD-L1增加，但PD-L2表面表达最小或检测不到。恶性WM细胞也有非常适度的PD-L1和PD-L2表面表达，表明配体从细胞表面裂解。患者骨髓血浆和血清中可溶性配体水平高于对照组。此外，IL-21和IL-6增加WM细胞系培养基中分泌的PD-L1，这意味着可溶性PD-1配体水平的升高是细胞因子介导的。可溶性PD-1配体降低T细胞增殖、磷酸化细胞外信号调节激酶和细胞周期蛋白A水平、线粒体三磷酸腺苷产生和备用呼吸能力。总之，我们发现WM患者中可溶性PD-1配体升高，并且除了WM BM中的表面结合配体之外，还可以调节T细胞功能。鉴于分泌形式在远端位点具有生物活性的能力，可溶性PD-1配体具有促进WM疾病进展的潜力。
Although immune checkpoint molecules regulate the progression of certain cancers, their significance in malignant development of Waldenstrom macroglobulinemia (WM), an incurable low-grade B-cell lymphoma, remains unknown. Recently, cytokines in the bone marrow (BM) microenvironment are shown to contribute to the pathobiology of WM. Here, we investigated the impact of cytokines, including interleukin-6 (IL-6) and IL-21, on immune regulation and particularly on the programmed death-1 (PD-1) and its ligands PD-L1 and PD-L2. We showed that IL-21, interferon gamma, and IL-6 significantly induced PD-L1 and PD-L2 gene expression in WM cell lines. Increased PD-L1 and PD-L2 messenger RNA was also detected in patients' BM cells. Patients' nonmalignant BM cells, including T cells and monocytes, showed increased PD-L1, but minimal or undetectable PD-L2 surface expression. There was also very modest PD-L1 and PD-L2 surface expression by malignant WM cells, suggesting that ligands are cleaved from the cell surface. Levels of soluble ligands were higher in patients' BM plasma and blood serum than controls. Furthermore, IL-21 and IL-6 increased secreted PD-L1 in the culture media of WM cell lines, implying that elevated levels of soluble PD-1 ligands are cytokine mediated. Soluble PD-1 ligands reduced T-cell proliferation, phosphorylated extracellular signal-regulated kinase and cyclin A levels, mitochondrial adenosine triphosphate production, and spare respiratory capacity. In conclusion, we identify that soluble PD-1 ligands are elevated in WM patients and, in addition to surface-bound ligands in WM BM, could regulate T-cell function. Given the capability of secreted forms to be bioactive at distant sites, soluble PD-1 ligands have the potential to promote disease progression in WM.