Immune Reactions against Gene Gun Vaccines Are Differentially Modulated by Distinct Dendritic Cell Subsets in the Skin.

The skin accommodates multiple dendritic cell (DC) subsets with remarkable functional diversity. Immune reactions are initiated and modulated by the triggering of DC by pathogen-associated or endogenous danger signals. In contrast to these processes, the influence of intrinsic features of protein antigens on the strength and type of immune responses is much less understood. Therefore, we investigated the involvement of distinct DC subsets in immune reactions against two structurally different model antigens, E. coli beta-galactosidase (betaGal) and chicken ovalbumin (OVA) under otherwise identical conditions. After epicutaneous administration of the respective DNA vaccines with a gene gun, wild type mice induced robust immune responses against both antigens. However, ablation of langerin+ DC almost abolished IgG1 and cytotoxic T lymphocytes against betaGal but enhanced T cell and antibody responses against OVA. We identified epidermal Langerhans cells (LC) as the subset responsible for the suppression of anti-OVA reactions and found regulatory T cells critically involved in this process. In contrast, reactions against betaGal were not affected by the selective elimination of LC, indicating that this antigen required a different langerin+ DC subset. The opposing findings obtained with OVA and betaGal vaccines were not due to immune-modulating activities of either the plasmid DNA or the antigen gene products, nor did the differential cellular localization, size or dose of the two proteins account for the opposite effects. Thus, skin-borne protein antigens may be differentially handled by distinct DC subsets, and, in this way, intrinsic features of the antigen can participate in immune modulation.

APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.

APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL. The inflammatory stimulus poly I:C, a toll-like receptor (TLR) 3 ligand, enhanced APRIL secretion. Silencing experiments decreased cell proliferation, demonstrating that APRIL is a critical autocrine factor for breast tumor growth. Studies of 4T1 orthotopic breast tumors in APRIL transgenic mice showed that an APRIL-enriched environment increased tumor growth and promoted lung metastasis associated with enhanced tumor cell proliferation; BCMA and TACI expression suggests that both participate in these processes. We detected APRIL, BCMA and TACI in human luminal, triple-negative breast carcinomas and HER2 breast carcinomas, with increased levels in more aggressive basal tumors. APRIL was observed near Ki67(+) nuclei and was distributed heterogeneously in the cancer cells, in the leukocyte infiltrate, and in the myoepithelial layer adjacent to the tumor area; these results imply that APRIL provides proliferation signals to tumor cells through paracrine and autocrine signaling. Our study identifies participation of APRIL signaling in breast cancer promotion; we propose impairment of this pathway as a potential therapeutic strategy.