Tumor stroma-associated antigens for anti-cancer immunotherapy

Immunotherapy has been widely investigated for its potential use in cancer therapy and it becomes more and more apparent that the selection of target antigens is essential for its efficacy. Indeed, limited clinical efficacy is partly due to immune evasion mechanisms of neoplastic cells, e.g. downregulation of expression or presentation of the respective antigens. Consequently, antigens contributing to tumor cell survival seem to be more suitable therapeutic targets. However, even such antigens may be subject to immune evasion due to impaired processing and cell surface expression. Since development and progression of tumors is not only dependent on cancer cells themselves but also on the active contribution of the stromal cells, e.g. by secreting growth supporting factors, enzymes degrading the extracellular matrix or angiogenic factors, the tumor stroma may also serve as a target for immune intervention. To this end several antigens have been identified which are induced or upregulated on the tumor stroma. Tumor stroma-associated antigens are characterized by an otherwise restricted expression pattern, particularly with respect to differentiated tissues, and they have been successfully targeted by passive and active immunotherapy in preclinical models. Moreover, some of these strategies have already been translated into clinical trials.     

Distinct, specific IL-17- and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response

We investigated whether the proinflammatory T cell cytokines IL-17 and IL-22 are induced by human mycobacterial infection. Remarkably, >20% of specific cytokine-producing CD4(+) T cells in peripheral blood of healthy, mycobacteria-exposed adults expressed IL-17 or IL-22. Specific IL-17- and IL-22-producing CD4(+) T cells were distinct from each other and from Th1 cytokine-producing cells. These cells had phenotypic characteristics of long-lived central memory cells. In patients with tuberculosis disease, peripheral blood frequencies of these cells were reduced, whereas bronchoalveolar lavage fluid contained higher levels of IL-22 protein compared with healthy controls. IL-17 was not detected in this fluid, which may be due to suppression by Th1 cytokines, as PBMC IL-17 production was inhibited by IFN-gamma in vitro. However, Th1 cytokines had no effect on IL-22 production in vitro. Our results imply that the magnitude and complexity of the anti-mycobacterial immune response have historically been underestimated. IL-17- and IL-22-producing CD4(+) T cells may play important roles in the human immune response to mycobacteria.     

Anti-cancer therapies targeting the tumor stroma

For anti-tumor therapy different strategies have been employed, e.g., radiotherapy, chemotherapy, or immunotherapy. Notably, these approaches do not only address the tumor cells themselves, but also the tumor stroma cells, e.g., endothelial cells, fibroblasts, and macrophages. This is of advantage, since these cells actively contribute to the proliferative and invasive behavior of the tumor cells via secretion of growth factors, angiogenic factors, cytokines, and proteolytic enzymes. In addition, tumor stroma cells take part in immune evasion mechanisms of cancer. Thus, approaches targeting the tumor stroma attract increasing attention as anti-cancer therapy. Several molecules including growth factors (e.g., VEGF, CTGF), growth factor receptors (CD105, VEGFRs), adhesion molecules (alphavbeta3 integrin), and enzymes (CAIX, FAPalpha, MMPs, PSMA, uPA) are induced or upregulated in the tumor microenvironment which are otherwise characterized by a restricted expression pattern in differentiated tissues. Consequently, these molecules can be targeted by inhibitors as well as by active and passive immunotherapy to treat cancer. Here we discuss the results of these approaches tested in preclinical models and clinical trials.     

Changes in the structure-function relationship of elastin and its impact on the proximal pulmonary arterial mechanics of hypertensive calves

Extracellular matrix remodeling has been proposed as one mechanism by which proximal pulmonary arteries stiffen during pulmonary arterial hypertension (PAH). Although some attention has been paid to the role of collagen and metallomatrix proteins in affecting vascular stiffness, much less work has been performed on changes in elastin structure-function relationships in PAH. Such work is warranted, given the importance of elastin as the structural protein primarily responsible for the passive elastic behavior of these conduit arteries. Here, we study structure-function relationships of fresh arterial tissue and purified arterial elastin from the main, left, and right pulmonary artery branches of normotensive and hypoxia-induced pulmonary hypertensive neonatal calves. PAH resulted in an average 81 and 72% increase in stiffness of fresh and digested tissue, respectively. Increase in stiffness appears most attributable to elevated elastic modulus, which increased 46 and 65%, respectively, for fresh and digested tissue. Comparison between fresh and digested tissues shows that, at 35% strain, a minimum of 48% of the arterial load is carried by elastin, and a minimum of 43% of the change in stiffness of arterial tissue is due to the change in elastin stiffness. Analysis of the stress-strain behavior revealed that PAH causes an increase in the strains associated with the physiological pressure range but had no effect on the strain of transition from elastin-dominant to collagen-dominant behavior. These results indicate that mechanobiological adaptations of the continuum and geometric properties of elastin, in response to PAH, significantly elevate the circumferential stiffness of proximal pulmonary arterial tissue.     

The influence of light and nutrient availability on herb layer species richness in oak-dominated forests in central Bohemia

In this study, we examined to what extent the internal site factors (light and soil conditions) are responsible for herb layer diversity in oak-dominated forest stands growing on different substrates in central Bohemia (Czech Republic). We collected data on herb layer diversity, light and nutrient availability at nine oak stands, representing the range of environmental variability for these types of forests in the region. We found that species richness increased with light availability, but only if the site occupied predominantly by fast-colonizing species was excluded from the analysis (P < 0.05). Species richness correlated positively with soil pH and negatively with nitrogen (N) concentration in humus (P < 0.05). The highest species richness was found at sites with not only low N soil concentration, but also simultaneously with high phosphorus (P) soil concentration. Despite this finding, however, herb layer diversity is evidently threatened much more in P-rich soils than in P-poor soils. It seems that the enhancement of N in an ecosystem due to litter accumulation and N deposition generally leads to only a minor increase in N availability at P-poor sites, but a considerable increase at P-rich sites. Therefore, species richness can be exceptionally high at P-rich sites, but only under conditions of strong N limitation.