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 stroma...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 thatα4β1 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.展开更多
基金in part supported by the National R&D Program for Cancer Control,the Ministry of Health and Welfare,the Republic of Korea(HA17C0040 to SIP)the National Research Foundation of the Republic of Korea(2018R1D1A1B07050329 and2020R1A2C1012966 to SIP,and 2020R1F1A1076996 to SPJ)the Korea University Research Grants(SIP)。
文摘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 thatα4β1 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.
