PDF(Pubmed)
Abstract：
Osteosarcoma (OS) is the most common primary bone malignancy and has a high propensity for local invasion and metastasis. The tumour microenvironment of OS is infiltrated by a large number of immune cells, which play a crucial role in its progression and prognosis. Mast cells are important innate immune cells in the tumour stroma and exhibit different phenotypes in diverse tumour microenvironments. However, the underlying mechanisms of mast cell accumulation and the phenotypic characteristics of mast cells in OS remain poorly understood. In this article, we found for the first time that mast cell accumulation in osteosarcoma tissue was modulated by the CXCL6-CXCR2 axis and that the number of infiltrating mast cells was significantly greater in tumour tissues than in adjacent nontumour tissues. These tumour-infiltrating mast cells express high levels of the immunosuppressive molecule PD-L2, and survival analyses revealed that patients in the PD-L2+ high-expression group had a worse prognosis. In vitro, mast cells were induced to express PD-L2 in a time- and dose-dependent manner using OS tissue culture supernatants to mimic the tumour microenvironment. Mechanistic studies revealed that tumour cell-derived G-CSF significantly induced mast cell PD-L2 expression by activating STAT3. Importantly, mast cells overexpressing PD-L2 inhibit tumour-specific CD8+ T-cell proliferation and tumour-killing cytokine secretion, which is reversed by blocking PD-L2 on mast cells. Therefore, our findings provide new insight into the immunosuppressive and tumorigenic roles of mast cells, as well as a novel mechanism by which PD-L2-expressing mast cells mediate immune tolerance.
摘要：
骨肉瘤（OS）是最常见的原发性骨恶性肿瘤，具有很高的局部侵袭和转移倾向。OS的肿瘤微环境被大量的免疫细胞浸润,在其进展和预后中起着至关重要的作用。肥大细胞是肿瘤基质中重要的先天免疫细胞，在不同的肿瘤微环境中表现出不同的表型。然而,肥大细胞积累的潜在机制和OS中肥大细胞的表型特征仍然知之甚少。在这篇文章中,我们首次发现,肥大细胞在骨肉瘤组织中的积累受到CXCL6-CXCR2轴的调节,并且肿瘤组织中的浸润肥大细胞数量显著高于邻近的非肿瘤组织.这些肿瘤浸润性肥大细胞表达高水平的免疫抑制分子PD-L2，生存分析显示PD-L2高表达组的患者预后较差。体外，使用OS组织培养上清液模拟肿瘤微环境,以时间和剂量依赖性方式诱导肥大细胞表达PD-L2。机制研究显示肿瘤细胞来源的G-CSF通过激活STAT3显著诱导肥大细胞PD-L2表达。重要的是,过表达PD-L2的肥大细胞抑制肿瘤特异性CD8+T细胞增殖和肿瘤杀伤细胞因子分泌，通过阻断肥大细胞上的PD-L2而逆转。因此,我们的发现为肥大细胞的免疫抑制和致瘤作用提供了新的见解，以及表达PD-L2的肥大细胞介导免疫耐受的新机制。
