Myeloid-derived Suppressor Cells Activate Liver Natural Killer Cells in a Murine Model in Uveal Melanoma

Objective Elevated myeloid-derived suppressor cells(MDSCs)in many malignancies are associated with the increased risk for metastases and poor prognosis.Therefore,a mouse model of intraocular melanoma was established to explore how MDSCs influence liver metastases.Methods In this study,murine B16LS melanoma cells were transplanted into the posterior compartment(PC)of the eye of C57BL/6 mice.Leucocytes from the liver of naive mice and mice bearing melanoma liver metastasis were isolated using isotonic Percoll centrifugation,examined by flow cytometry for their expression of Gr1,CD11b,F4/80,RAE-1,and Mult-1,and further isolated for MDSCs and natural killer(NK)cells.The effects of MDSCs on NK cells were tested by coculturing and assessing the ability of NK cells to produce interferon-gamma(IFN-γ)by ELISA and NK cell cytotoxicity by 3H-thymidine incorporation assay.The impact of IFN-γon liver metastases was examined via selectively depleting IFN-γin vivo.Results The results showed that mice with liver metastases had increased levels of CD11b+Gr1+F4/80+as well as CD11b+Gr1+F4/80−MDSCs.MDSCs significantly enhanced the generation of IFN-γtogether with the cytotoxicity of the NK cells.Furthermore,these effects were cell-cell contact-dependent.Although IFN-γwas not of a toxic nature to the melanoma cells,it profoundly inhibited B16LS cell proliferation.Depleting IFN-γin vivo led to increased liver metastases.Conclusion All these findings first revealed that MDSCs accumulated in liver metastasis of intraocular melanoma could activate the NK cells to produce an effective anti-tumor immune response.Thus,the MDSCs’performance in different tumor models would need more investigation to boost current immunotherapy modalities.

Discovery of the mid-Cretaceous sedimentary rocks from the ultrahigh-pressure terrane,Dabie Orogenic Belt,and its tectonopaleogeographic implications

The Dabie Orogenic Belt, located in east-central China, is known for the greatest outcrop area of the ultrahigh-pressure metamorphic rocks in the world and is typical for studying deep continental subduction and continent-continent collision. However, since lower-grade metamorphic rock occurrence in the core of the ultrahigh-pressure terrane was reported, it has become a new point of concern. This study reported new results. The so-called lower-grade metamorphic rocks are divided into sedimentary rocks and meta-volcanics.The sedimentary rocks consist mainly of fine-grained turbidites formed under an anoxic deep-water lacustrine basin. Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry U-Pb detrital zircon dating indicates that their maximum deposit age is 119.0 ± 1.1 Ma belonging to the mid-Cretaceous Aptian. U-Pb detrital zircon ages from the sedimentary rocks cluster in three age groups: 1) 2773.8-1550.0 Ma(45.0%);2)868.8-622.3 Ma(23.0%);3) 147.0-100.0 Ma(31.5%). And the provenance and tectonic settings of these sedimentary rocks are discussed by synthesizing U-Pb detrital zircon ages, initial Hf isotope ratios, and trace elements of the zircons. Source rocks of the first group were mainly composed of the Paleoproterozoic basement derived from the reworking of the Paleoarchean-Neoarchean Yangtze continental crust. For the second group, its source rocks consisted of Neoproterozoic volcanics mainly from an island arc system, which derived from the reworking of older continental crust in the northern Yangtze Block. The third group’s source rocks were chiefly composed of Cretaceous rift igneous rocks derived from the derivation through melting of middle-aged continental crust in the Dabie Orogenic Belt. The meta-volcanics have weighted mean U-Pb ages from 751.0 ± 16 Ma to 786.3 ± 5.9 Ma, and their protoliths formed under a Middle Neoproterozoic island arc system in the northern Yangtze Block. The meta-volcanics underwent a Triassic subduction of different depths and then an exhumation, but the sedimentary rocks did not. The findings suggest that the ultrahigh-pressure terrane had suffered violent subsidence during the mid-Cretaceous, and a four-stage evolution model of the Dabie Orogenic Belt was established accordingly.