Physiological Role of Plasmacytoid Dendritic Cells and Their Potential Use in Cancer Immunity

Dendritic cells (DCs) play a pivotal role in the control of innate and adaptive immune responses. They are a heterogeneous cell population, where plasmacytoid dendritic cells (pDCs) are a unique subset capable of secreting high levels of type I IFNs. It has been demonstrated that pDCs can coordinate events during the course of viral infection, atopy, autoimmune diseases, and cancer. Therefore, pDC, as a main source of type I IFN, is an attractive target for therapeutic manipulations of the immune system to elicit a powerful immune response against tumor antigens in combination with other therapies. The therapeutic vaccination with antigen-pulsed DCs has shown a limited efficacy to generate an effective long-lasting immune response against tumor cells. A rational manipulation and design of vaccines which could include DC subsets outside “Langerhans cell paradigm” might allow us to improve the therapeutic approaches for cancer patients

Thermal conductivity of iron and nickel during melting: Implication to Planetary liquid outer core

We report the measurements of the thermal conductivity ($\kappa$) of iron (Fe) and nickel (Ni) at high pressures and high temperatures. $\kappa$ values are estimated from the temperature measurements across the sample surface in a laser heated diamond anvil cell (LHDAC) and using the COMSOL software. Near-isothermal $\kappa$'s are observed to increase with pressure in both the metals due to the increase of density of the pressed metals. In both metals $\kappa$'s are observed to follow a sharp fall during melting at different pressure points and are consistence with the other multi-anvil measurements. Constant values of $\kappa$ in these metals during melting at different pressures reveal the loss of long range order, which creates independent movement of atomic metals. The melting temperature measured in these metals from the sudden drop of $\kappa$-values are in a good agreement with the other melting measurements in LHDAC. The results obtained in this study is expected to provide an insight to the studies on the planets Mercury and Mars and their interior

Breast Cancer Associated Metastasis is Significantly Increased in a Model of Autoimmune Arthritis

Chronic inflammation is known to play a role in cancer initiation, promotion,and metastasis. However, the mechanism by which inflammation promotes metastasis is still unclear. We evaluated if chronic inflammation induced by autoimmune arthritis may contribute to increased breast cancer-associated metastasis. We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic mice compared to control mice. The metastatic breast tumors in turn augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as IL-17, IL-6, VEGF, and TNF-α were the underlying factors contributing to the increased metastasis. The data clearly has important clinical implications for patients diagnosed with metastatic breast cancer

Exacerbated metastatic disease in a mouse mammary tumor model following latent gammaherpesvirus infection

BACKGROUND: Controversy exists as to the ability of human gammaherpesviruses to cause or exacerbate breast cancer disease in patients. The difficulty in conducting definitive human studies can be overcome by investigating developing breast cancer in a mouse model. In this study, we utilized mice latently infected with murine gammaherpesvirus 68 (HV-68) to question whether such a viral burden could exacerbate metastatic breast cancer disease using a mouse mammary tumor model. RESULTS: Mice latently infected with HV-68 had a similar primary tumor burden, but much greater metastatic disease, when compared to mock treated mice given the transplantable tumor, 4 T1. This was true for lung lesions, as well as secondary tumor masses. Increased expression of pan-cytokeratin and VEGF-A in tumors from HV-68 infected mice was consistent with increased metastatic disease in these animals. Surprisingly, no viral particles could be cultured from tumor tissues, and the presence of viral DNA or RNA transcripts could not be detected in primary or secondary tumor tissues. CONCLUSIONS: Latent HV-68 infection had no significant effect on the size of primary 4 T1 mammary tumors, but exacerbated the number of metastatic lung lesions and secondary tumors when compared to mock treated mice. Increased expression of the tumor marker, pan-cytokeratin, and VEGF-A in tumors of mice harboring latent virus was consistent with an exacerbated metastatic disease. Mechanisms responsible for this exacerbation are indirect, since no virus could be detected in cancerous tissues

Combining the Specific Anti-MUC1 Antibody TAB004 and Lip-MSA-IL-2 Limits Pancreatic Cancer Progression in Immune Competent Murine Models of Pancreatic Ductal Adenocarcinoma

Immunotherapy regimens have shown success in subsets of cancer patients; however, their efficacy against pancreatic ductal adenocarcinoma (PDA) remain unclear. Previously, we demonstrated the potential of TAB004, a monoclonal antibody targeting the unique tumor-associated form of MUC1 (tMUC1) in the early detection of PDA. In this study, we evaluated the therapeutic benefit of combining the TAB004 antibody with Liposomal-MSA-IL-2 in immune competent and human MUC1 transgenic (MUC1.Tg) mouse models of PDA and investigated the associated immune responses. Treatment with TAB004 + Lip-MSA-IL-2 resulted in significantly improved survival and slower tumor growth compared to controls in MUC1.Tg mice bearing an orthotopic PDA.MUC1 tumor. Similarly, in the spontaneous model of PDA that expresses human MUC1, the combination treatment stalled the progression of pancreatic intraepithelial pre-neoplastic (PanIN) lesion to adenocarcinoma. Treatment with the combination elicited a robust systemic and tumor-specific immune response with (a) increased percentages of systemic and tumor infiltrated CD45+CD11b+ cells, (b) increased levels of myeloperoxidase (MPO), (c) increased antibody-dependent cellular cytotoxicity/phagocytosis (ADCC/ADCP), (d) decreased percentage of immune regulatory cells (CD8+CD69+ cells), and (e) reduced circulating levels of immunosuppressive tMUC1. We report that treatment with a novel antibody against tMUC1 in combination with a unique formulation of IL-2 can improve survival and lead to stable disease in appropriate models of PDA by reducing tumor-induced immune regulation and promoting recruitment of CD45+CD11b+ cells, thereby enhancing ADCC/ADCP