IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses.

Previous studies have provided evidence that IL-15 expression within human tumors is crucial for optimal antitumor responses; however, the regulation of IL-15 within the tumor microenvironment (TME) is unclear. We report herein, in analyses of mice implanted with various tumor cell lines, soluble IL-15/IL-15Rα complexes (sIL-15 complexes) are abundant in the interstitial fluid of tumors with expression preceding the infiltration of tumor-infiltrating lymphocytes. Moreover, IL-15 as well as type I IFN, which regulates IL-15, was required for establishing normal numbers of CD8 T cells and natural killer cells in tumors. Depending on tumor type, both the tumor and the stroma are sources of sIL-15 complexes. In analyses of IL-15 reporter mice, most myeloid cells in the TME express IL-15 with CD11b+Ly6Chi cells being the most abundant, indicating there is a large source of IL-15 protein in tumors that lies sequestered within the tumor stroma. Despite the abundance of IL-15-expressing cells, the relative levels of sIL-15 complexes are low in advanced tumors but can be up-regulated by local stimulator of IFN genes (STING) activation. Furthermore, while treatment of tumors with STING agonists leads to tumor regression, optimal STING-mediated immunity and regression of distant secondary tumors required IL-15 expression. Overall, our study reveals the dynamic regulation of IL-15 in the TME and its importance in antitumor immunity. These findings provide insight into an unappreciated attribute of the tumor landscape that contributes to antitumor immunity, which can be manipulated therapeutically to enhance antitumor responses.

Impaired glucose tolerance predicts all-cause mortality among older men at high risk for cardiovascular disease in China.

AIMS: To investigate the potential association between impaired glucose tolerance (IGT) and all-cause mortality among older men at high risk for cardiovascular disease (CVD) in China. METHODS: In this prospective observational study, 460 older men aged ≥60 years were determined to have either IGT or normal glucose tolerance (NGT) based on an oral glucose tolerance test conducted between May 2005 and May 2007. IGT and NGT were diagnosed according to the 1999 WHO diagnostic criteria. All subjects were followed until March 2017. The primary outcome studied was all-cause mortality. Multivariate Cox models were used to estimate relative risk for all-cause mortality. RESULTS: During a mean follow-up of 11.2 years, forty-three (21.4%) subjects in the IGT group and twenty-nine (11.2%) subjects in the NGT group died (HR 2.05, 95% CI 1.28-3.28, P=0.003). Multivariate Cox proportional-hazards analysis demonstated that IGT was significantly associated with increased risk for all-cause mortality, composite cardiovascular outcome, nonfatal stroke and heart failure after adjusting for potential confounding factors. Logistic regression analysis showed that IGT at baseline (P<0.05) rather than incident type 2 diabetes was a risk factor of all-cause mortality. CONCLUSIONS: IGT was significantly associated with all-cause mortality in older Chinese men at high risk for CVD.