Tumor-derived extracellular vesicles activate primary monocytes.

Tumor cells educate immune effector cells in their vicinity by releasing factors that manipulate their phenotype and function. In fact, the thus generated immunosuppressive tumor microenvironment constitutes an integral part and a hallmark of solid tumors and contributes significantly to tumor development and immune escape. It has long been thought that soluble factors like prostaglandin E2 and TGF-ß are the main mediators of these effects. But tumor cells also constantly release large number of extracellular vesicles (EVs), which are important conveyors of immune responses. We show here that tumor-derived EVs interact with primary monocytes and induce an activated phenotype, which is also observed in tumor-associated macrophages. Thus, both tumor-derived EVs and soluble factors together collaborate to form the immunosuppressive milieu of the tumor environment.

Generation and characterization of the first inhibitory antibody targeting tumour-associated carbonic anhydrase XII.

The carbonic anhydrases (CAs) constitute a family of almost ubiquitous enzymes of significant importance for many physiological and pathological processes. CAs reversely catalyse the conversion of CO(2) + H(2)O to HCO(3) (-) and H(+), thereby contributing to the regulation of intracellular pH. Above all, CAs are of key importance for cells that perform glycolysis that inevitably leads to the intracellular accumulation of lactate. CA XII is a plasma membrane-associated isoform of the enzyme, which is induced by hypoxia and oestrogen and, consequently, expressed at high levels on various types of cancer and, intriguingly, on cancer stem cells. The enzyme is directly involved in tumour progression, and its inhibition has an anti-tumour effect. Apart from its role in carcinogenesis, the enzyme contributes to various other diseases like glaucoma and arteriosclerotic plaques, among others. CA XII is therefore regarded as promising target for specific therapies. We have now generated the first monoclonal antibody (6A10) that binds to the catalytic domain of CA XII on vital tumour cells and inhibits CA XII enzyme activity at nanomolar concentrations and thus much more effective than acetazolamide. In vitro results demonstrate that inhibition of CA XII by 6A10 inhibits the growth of tumour cells in 3-dimensional structures. In conclusion, we generated the first specific and efficient biological inhibitor of tumour-associated CA XII. This antibody may serve as a valuable tool for in vivo diagnosis and adjuvant treatment of different types of cancer.

Tumour exosomes inhibit binding of tumour-reactive antibodies to tumour cells and reduce ADCC.

In order to grow within an immunocompetent host, tumour cells have evolved various strategies to cope with the host's immune system. These strategies include the downregulation of surface molecules and the secretion of immunosuppressive factors like IL-10 and PGE2 that impair the maturation of immune effector cells, among other mechanisms. Recently, tumour exosomes (TEX) have also been implicated in tumour-induced immune suppression as it has been shown that TEX can induce apoptosis in T lymphocytes. In this study, we extend our knowledge about immunosuppressive features of these microvesicles in that we show that TEX efficiently bind and sequester tumour-reactive antibodies and dramatically reduce their binding to tumour cells. Moreover, we demonstrate that this antibody sequestration reduces the antibody-dependent cytotoxicity by immune effector cells, which is among the most important anti-tumour reactions of the immune system and a significant activity of therapeutic antibodies. Taken together, these data point to the fact that tumour-derived exosomes interfere with the tumour-specific function of immune cells and constitute an additional mechanism how tumours escape from immune surveillance.