Extracellular matrix educates an immunoregulatory tumor macrophage phenotype found in ovarian cancer metastasis.

Recent studies have shown that the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and responsiveness to immunotherapy. A question that remains unresolved is whether the ECM directly educates the immune phenotypes seen in tumors. Here, we identify a tumor-associated macrophage (TAM) population associated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether the ECM was capable of generating this TAM phenotype, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissue. ECM-educated macrophages have a tissue-remodeling and immunoregulatory phenotype, inducing altered T cell marker expression and proliferation. We conclude that the tumor ECM directly educates this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

The role of the inflammasome in fibrotic respiratory diseases.

Fibrotic respiratory diseases severely disrupt lung function and currently have an extremely poor prognosis. This is attributable to the limited amount of treatment options available, in part due to our lack of understanding of the mechanisms driving disease pathogenesis. Although the majority of cases appear to be idiopathic, a number of factors are known to cause pulmonary fibrosis, such as the inhalation of silica crystals (silicosis), asbestos fibers (asbestosis) and certain drugs such as bleomycin. Evidence suggests that the inhalation of such substances can induce the formation of the NLRP3 inflammasome; a multimeric protein complex responsible for the activation of caspase-1 and maturation of the proinflammatory cytokines IL-1b and IL-18. Moreover, data suggests that inhibition of the inflammasome activation pathway and/or inflammasome-mediated cytokines can attenuate the fibrotic response in in vitro and in vivo models of disease. In this review, we discuss the evidence suggesting that the NLRP3 inflammasome plays an important role in the pathogenesis of fibrotic respiratory diseases, and the potential mechanisms by which activation of the NLRP3 inflammasome may occur. It is possible that fibrotic respiratory diseases with a known cause may share a common mechanism with idiopathic pulmonary fibrosis, providing possible strategies for future drug therapies.

Modulating effects of interferon preparations on an antibody response in vitro.

The effect of mouse interferon preparations on the primary in vitro antibody response of mouse spleen cells was studied. Concentrations of interferon greater than 8 units per ml significantly inhibited the antibody response while low concentrations of 0-08-0-8 units per ml could be shown to be mildly enhancing. Various treatments which affected the antiviral activity of the interferon preparations reduced the immunosuppressive activity to a similar extent. Interferon acts during the first few hours of a response but the effect is not apparent for at least 50 h. Interferon had no effect when added after 48 h. The kinetic data has been interpreted as demonstrating interferon-sensitive and interferon-resistant components of the in vitro response. The results from investigations of the polyclonal response to lipopolysaccharide support the view that interferon acts mainly on B cells alone, although effects on T-B interactions cannot be excluded.