The breaking of immune tolerance against autologous angiogenic endothelial cells should be a useful approach for cancer therapy. Here we show that immunotherapy of tumors using fixed xenogeneic whole endothelial cells as a vaccine was effective in affording protection from tumor growth, inducing regression of established tumors and prolonging survival of tumor-bearing mice. Furthermore, autoreactive immunity targeting to microvessels in solid tumors was induced and was probably responsible for the anti-tumor activity. These observations may provide a new vaccine strategy for cancer therapy through the induction of an autoimmune response against the tumor endothelium in a cross-reaction.

The Hippo pathway plays a critical role in cell growth and tumorigenesis. The activity of TEA domain transcription factor 4 (TEAD4) determines the output of Hippo signaling; however, the regulation and function of TEAD4 has not been explored extensively. Here, we identified glucocorticoids (GC) as novel activators of TEAD4. GC treatment facilitated glucocorticoid receptor (GR)-dependent nuclear accumulation and transcriptional activation of TEAD4. TEAD4 positively correlated with GR expression in human breast cancer, and high expression of TEAD4 predicted poor survival of patients with breast cancer. Mechanistically, GC activation promoted GR interaction with TEAD4, forming a complex that was recruited to the TEAD4 promoter to boost its own expression. Functionally, the activation of TEAD4 by GC promoted breast cancer stem cells maintenance, cell survival, metastasis, and chemoresistance both in vitro and in vivo. Pharmacologic inhibition of TEAD4 inhibited GC-induced breast cancer chemoresistance. In conclusion, our study reveals a novel regulation and functional role of TEAD4 in breast cancer and proposes a potential new strategy for breast cancer therapy. Significance: This study provides new insight into the role of glucocorticoid signaling in breast cancer, with potential for clinical translation.

Entry of opsonized pathogens into phagocytes may benefit or, paradoxically, harm the host. Opsonization may trigger antimicrobial mechanisms such as reactive oxygen or nitric oxide (NO) production but may also provide a safe haven for intracellular replication. Brucellae are natural intramacrophage pathogens of rodents, ruminants, dogs, marine mammals, and humans. We evaluated the role of opsonins in Brucellamacrophage interactions by challenging cultured murine peritoneal macrophages with Brucella melitensis 16M treated with complement-and/or antibody-rich serum. Mouse serum rich in antibody against Brucella lipopolysaccharide (LPS) (aLPS) and human complement-rich serum (HCS) each enhanced the macrophage uptake of brucellae. Combinations of suboptimal levels of aLPS (0.01%) and HCS (2%) synergistically enhanced uptake. The intracellular fate of ingested bacteria was evaluated with an optimal concentration of gentamicin (2 g/ml) to control extracellular growth but not kill intracellular bacteria. Bacteria opsonized with aLPS and/or HCS grew equally well inside macrophages in the absence of gamma interferon (IFN-␥). Macrophage activation with IFN-␥ inhibited replication of both opsonized and nonopsonized brucellae but was less effective in inhibiting replication of nonopsonized bacteria. IFN-␥ treatment of macrophages with opsonized or nonopsonized bacteria enhanced NO production, which was blocked by N G -monomethyl L-arginine (MMLA), an NO synthesis inhibitor. MMLA also partially blocked IFN-␥-mediated bacterial growth inhibition. These studies suggest that primary murine macrophages have limited ability to control infection with B. melitensis, even when activated by IFN-␥ in the presence of highly opsonic concentrations of antibody and complement. Additional cellular immune responses, e.g., those mediated by cytotoxic T cells, may play more important roles in the control of murine brucellosis.Brucella spp., short, nonmotile, nonsporulating, nonencapsulated, gram-negative aerobic rods, are important facultative intracellular pathogens of humans and livestock. Brucella melitensis usually infects sheep, goats, and camels and is the most pathogenic species for humans (1). Like other facultative intracellular pathogenic bacteria (e.g., Francisella tularensis, Listeria monocytogenes, Mycobacterium spp., and Legionella pneumophila), clearance of Brucella infection relies on both cellmediated immunity (1,3,7,12,20,21,27,30,38) and humoral responses (10,22,29,35). The interplay of these two arms of the immune response, however, is not well understood.Successful infection of the host by Brucella reflects the ability of the bacterium to establish itself in an intracellular environment favorable for its replication. The presence of complement or antibody in the extracellular fluid favors killing of some Brucella strains (35,38). Opsonization by these humoral factors also enhances uptake by phagocytic cells that shelter the bacteria. The intracellular fate of brucellae may depend on the bacterial species or the kind of ph...

Highlights d YAP represses NR4A1 transcription and mitochondrial localization d NR4A1 mediates the pro-apoptotic function in response to Hippo signaling d NR4A1 promotes YAP degradation to augment Hippo signaling d YAP promotes liver regeneration and tumorigenesis by repressing NR4A1

We previously showed that a purE mutant (⌬purE201) of Brucella melitensis 16M is attenuated for growth in cultured human monocytes (E.