Lee Eun Jung, Lee Kyoung Jin, Jung Seungpil, Park Kyong Hwa, Park Serk In
Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, Republic of Korea.
The BK21 Graduate Program, Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Republic of Korea.
Bone Res. 2023 Apr 21;11(1):22. doi: 10.1038/s41413-023-00255-y.
Myeloid-derived suppressor cells (MDSCs) are bone marrow (BM)-derived immunosuppressive cells in the tumor microenvironment, but the mechanism of MDSC mobilization from the BM remains unclear. We investigated how BM stromal cell activation by PTH1R contributes to MDSC mobilization. PTH1R activation by parathyroid hormone (PTH) or PTH-related peptide (PTHrP), a tumor-derived counterpart, mobilized monocytic (M-) MDSCs from murine BM without increasing immunosuppressive activity. In vitro cell-binding assays demonstrated that α4β1 integrin and vascular cell adhesion molecule (VCAM)-1, expressed on M-MDSCs and osteoblasts, respectively, are key to M-MDSC binding to osteoblasts. Upon PTH1R activation, osteoblasts express VEGF-A and IL6, leading to Src family kinase phosphorylation in M-MDSCs. Src inhibitors suppressed PTHrP-induced MDSC mobilization, and Src activation in M-MDSCs upregulated two proteases, ADAM-17 and MMP7, leading to VCAM1 shedding and subsequent disruption of M-MDSC tethering to osteoblasts. Collectively, our data provide the molecular mechanism of M-MDSC mobilization in the bones of tumor hosts.
髓系来源的抑制性细胞（MDSCs）是肿瘤微环境中源自骨髓（BM）的免疫抑制细胞，但MDSCs从骨髓中动员的机制仍不清楚。我们研究了甲状旁腺激素1型受体（PTH1R）激活骨髓基质细胞如何促进MDSCs的动员。甲状旁腺激素（PTH）或肿瘤来源的对应物甲状旁腺激素相关肽（PTHrP）激活PTH1R，可从小鼠骨髓中动员单核细胞（M-）MDSCs，而不增加免疫抑制活性。体外细胞结合试验表明，分别在M-MDSCs和成骨细胞上表达的α4β1整合素和血管细胞黏附分子（VCAM）-1是M-MDSC与成骨细胞结合的关键。PTH1R激活后，成骨细胞表达血管内皮生长因子A（VEGF-A）和白细胞介素6（IL6），导致M-MDSCs中的Src家族激酶磷酸化。Src抑制剂抑制PTHrP诱导的MDSC动员，M-MDSCs中的Src激活上调两种蛋白酶，即解聚素和金属蛋白酶17（ADAM-17）和基质金属蛋白酶7（MMP7），导致VCAM1脱落，随后破坏M-MDSC与成骨细胞的连接。总体而言，我们的数据揭示了肿瘤宿主骨骼中M-MDSC动员的分子机制。
