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The glucocorticoid-induced tumor necrosis factor receptor (GITR) agonistic antibody (DTA-1) has been proved to elicit robust immune response in various kinds of tumors. However, only a few of the HCC patients could benefit from it, and the mechanism of DTA-1 resistance remains unknown. Here, we measured GITR expression in different immunocytes in HCC microenvironment, and we observed that tumor-infiltrating regulatory T cells (Ti-Tregs) significantly expressed GITR, which were associated with poor prognosis. Meanwhile, we analyzed the variation of tumor-infiltrating immune components and associated inflammation response after DTA-1 treatment in orthotopic liver cancer model of mice. Surprisingly, DTA-1 treatment reduced the infiltration of Tregs but failed to activate CD8+ T cells and elicit antitumor efficacy. In particular, DTA-1 treatment enforced alternative M2 polarization of macrophage, and macrophage depletion could enhance DTA-1-mediated antitumor efficacy in HCC. Mechanistically, macrophage M2 polarization attributed to the IL-4 elevation induced by Th2 immune activation in the treatment of DTA-1, resulting in DTA-1 resistance. Furthermore, Toll-like receptor 4 (TLR4) agonist could diminish the macrophage (M2) polarization and reverse the M2-mediated DTA-1 resistance, eliciting robust antitumor effect in HCC. Our finding demonstrated that the TLR4 agonist synergized with DTA-1 was a potential strategy for HCC treatment.

The expression of the SRY-Box Transcription Factor 15 (Sox15) is reduced by DNA methylation, and its progression is suppressed within numerous tumors. However, its effect on hepatocellular carcinoma (HCC) remains unknown. In the present work, the clinical importance and function of Sox15, as well as the underlying molecular mechanism, were explored within HCC. The expression of Sox15 is reduced and positively correlated with prognosis in HCC as analyzed by GEPIA (Gene Expression Profiling Interactive Analysis) and OncoLnc. Meanwhile, the hypermethylated Sox15 promoter CpG-site predicted a dismal HCC prognosis. Besides, ectopic Sox15 expression within the HCC cells (LM3, HUH7, SK-hep-1) remarkably inhibited in vitro cell growth and inhibited xenograft tumorigenesis in the nude mice. Moreover, Sox15 inactivated the Wnt pathway under both in vivo and in vitro conditions. To summarize, Sox15 played a tumor suppressor role within the HCC via the inactivated Wnt pathway. Sox15 and CpG-site methylation of its promoter are the factors that independently predict the prognosis of HCC.

Objective To establish a nude mouse model of photoaging and study the therapeutic effect of a concentrated growth factor preparation (CGF) on skin photoaging. Methods CGF was prepared from blood from Sprague–Dawley rats. A skin photoaging nude mouse model was developed using UV irradiation combined with the photosensitizer, 8-methoxypsoralen. Mice were divided randomly into seven groups (n = 6 per group): normal control, photoaging, mock treatment, saline treatment, CGF treatment, Filoca 135HA treatment, and plasma skin regeneration system irradiation (the latter two were positive controls). Body weight and skin appearance were observed and pathological changes were determined by hematoxylin and eosin staining. Fiber elasticity was evaluated by Weigert staining. Expression levels of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase 1 (MMP1) were determined by immunohistochemistry. Results A mouse model with typical features of photoaging skin was successfully developed. CGF significantly improved the skin appearance, wrinkle scores, pathological changes, and fiber elasticity, and increased PCNA and decreased MMP1 expression levels in photoaging mice, comparable to the two positive controls. Conclusion CGF can improve the symptoms of skin photoaging in mice, suggesting that it may have applications in the treatment of skin aging in humans.