25 research outputs found
Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity
SummarySpontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells. On the basis of recent observations indicating that IFN-β expression was dependent upon activation of the host STING pathway, we hypothesized that direct engagement of STING through intratumoral (IT) administration of specific agonists would result in effective anti-tumor therapy. After proof-of-principle studies using the mouse STING agonist DMXAA showed a potent therapeutic effect, we generated synthetic cyclic dinucleotide (CDN) derivatives that activated all human STING alleles as well as murine STING. IT injection of STING agonists induced profound regression of established tumors in mice and generated substantial systemic immune responses capable of rejecting distant metastases and providing long-lived immunologic memory. Synthetic CDNs have high translational potential as a cancer therapeutic
CD1d-Expressing Breast Cancer Cells Modulate NKT Cell-Mediated Antitumor Immunity in a Murine Model of Breast Cancer Metastasis
Tumor tolerance and immune suppression remain formidable obstacles to the efficacy of immunotherapies that harness the immune system to eradicate breast cancer. A novel syngeneic mouse model of breast cancer metastasis was developed in our lab to investigate mechanisms of immune regulation of breast cancer. Comparative analysis of low-metastatic vs. highly metastatic tumor cells isolated from these mice revealed several important genetic alterations related to immune control of cancer, including a significant downregulation of cd1d1 in the highly metastatic tumor cells. The cd1d1 gene in mice encodes the MHC class I-like molecule CD1d, which presents glycolipid antigens to a specialized subset of T cells known as natural killer T (NKT) cells. We hypothesize that breast cancer cells, through downregulation of CD1d and subsequent evasion of NKT-mediated antitumor immunity, gain increased potential for metastatic tumor progression.In this study, we demonstrate in a mouse model of breast cancer metastasis that tumor downregulation of CD1d inhibits iNKT-mediated antitumor immunity and promotes metastatic breast cancer progression in a CD1d-dependent manner in vitro and in vivo. Using NKT-deficient transgenic mouse models, we demonstrate important differences between type I and type II NKT cells in their ability to regulate antitumor immunity of CD1d-expressing breast tumors.The results of this study emphasize the importance of determining the CD1d expression status of the tumor when tailoring NKT-based immunotherapies for the prevention and treatment of metastatic breast cancer
Sprouty Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C
PLCγ03B3 binds Spry1 and Spry2. Overexpression of Spry decreased PLCγ03B3 activity and IP3 and DAG production, whereas Spry-deficient cells yielded more IP3. Spry overexpression inhibited T-cell receptor signaling and Spry1 null T-cells hyperproliferated with TCR ligation. Through action of PLCγ03B3, Spry may influence signaling through multiple receptors
Government-Opposition Dynamics in Spain under the Pressure of Economic Collapse and the Debt Crisis
Government - opposition relations in Spain have been long characterised by a high level of consensus and cooperation. The question analysed here is whether the economic crisis initiated in 2008 has created unprecedented levels of conflict in the political system or whether opposition parties have maintained a cooperative strategy oriented to influence far-reaching policy decisions. Results illustrate that patterns of consensus have decreased significantly since the outbreak of the crisis, and this is partly explained by the rising amount of legislation with socio-economic content, variations in the government's popularity, and the type of government. The analysis also shows that the crisis has increased the incentives of opposition parliamentary groups to oppose European Union legislation, especially among left parties
The Effects of Urbanization on Leaf Breakdown Rates in a Rock Island Watershed
The ability of streams to break down leaves is widely used as an indicator of stream health. In this study, a series of six streams within the Rock Island, Ill., watershed, which were similar in discharge, order, temperature and pH, were categorized as healthy or unhealthy based on chloride levels. This study was part of a broader study of the Rock Island watershed by Augustana. Maple leaves were collected shortly after abscission, weighed, packaged in mesh bags (approximately 5g per bag) and deployed in the streams for two- and four-week periods. After each time period, the leaves were removed, dried and weighed, and the mass loss was calculated as well as overall leaf decomposition rate. The healthy streams decomposed leaves significantly faster than the unhealthy streams. These results suggest that streams in close proximity to impervious surfaces (the unhealthy streams) experienced a loss of the ecosystem service of leaf decomposition perhaps due to a loss of invertebrate shredders because of high chloride levels associated with urbanization
Regulation of COX2 expression in mouse mammary tumor cells controls bone metastasis and PGE2-induction of regulatory T cell migration.
BACKGROUND: The targeting of the immune system through immunotherapies to prevent tumor tolerance and immune suppression are at the front lines of breast cancer treatment and research. Human and laboratory studies have attributed breast cancer progression and metastasis to secondary organs such as the bone, to a number of factors, including elevated levels of prostaglandin E2 (PGE2) and the enzyme responsible for its production, cyclooxygenase 2 (COX2). Due to the strong connection of COX2 with immune function, we focused on understanding how variance in COX2 expression manipulates the immune profile in a syngeneic, and immune-competent, mouse model of breast cancer. Though there have been correlative findings linking elevated levels of COX2 and Tregs in other cancer models, we sought to elucidate the mechanisms by which these immuno-suppressive cells are recruited to breast tumor and the means by which they promote tumor tolerance. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the mechanisms by which exacerbated COX2 expression potentiates metastasis we genetically manipulated non-metastatic mammary tumor cells (TM40D) to over-express COX2 (TM40D-COX2). Over-expression of COX2 in this mouse breast cancer model resulted in an increase in bone metastasis (an observation that was ablated following suppression of COX2 expression) in addition to an exacerbated Treg recruitment in the primary tumor. Interestingly, other immune-suppressive leukocytes, such as myeloid derived suppressor cells, were not altered in the primary tumor or the circulation. Elevated levels of PGE2 by tumor cells can directly recruit CD4+CD25+ cells through interactions with their EP2 and/or EP4 receptors, an effect that was blocked using anti-PGE2 antibody. Furthermore, increased Treg recruitment to the primary tumor contributed to the greater levels of apoptotic CD8+ T cells in the TM40D-COX2 tumors. CONCLUSION/SIGNIFICANCE: Due to the systemic effects of COX2 inhibitors, we propose targeting specific EP receptors as therapeutic interventions to breast cancer progression
Regulation of COX2 Expression in Mouse Mammary Tumor Cells Controls Bone Metastasis and PGE2-Induction of Regulatory T Cell Migration
TM40D-COX2 tumors preferentially recruit Tregs to the tumor.
<p>Histological sections of TM40D and TM40D-COX2 tumors were stained with (A and B) H&E or (C and D) AlexaFluor 594 for CD4 (RED) AlexaFluor 488 for FoxP3 (GREEN), or Dapi for nucleus (BLUE). Arrows in panels C and D represent Tregs. E. Quantitative analysis of panels C and D measuring the percent of CD4+ cells that have FoxP3 co-localized to the cell. N = 3 samples per group, 8–10 sections per sample. *p<0.01 compared to TM40D. Bar = 20 µm.</p
PGE2 directly involved in inducing Treg migration.
<p>CD4+ CD25+ Tregs were enriched by magnetic column (MACS) from naïve thymus and lymph nodes (A). Treg migration was measured using media alone, cell-free supernatant collected from TM40D, TM40D-COX2, or TM40D-MB cells (B). Additionally, the role of PGE2 was assessed by anti-PGE2 blocking antibody added to TM40D-COX2 media. Purified GFP-FoxP3+ cells were isolated from spleen following CD4+ T cell enrichment (C) and analyzed for expression of the PGE2 receptors EP1, EP2, EP3, or EP4 via RT-PCR with GAPDH as a control (D). #p<0.05, *p<0.01 compared to Media alone, N = 3 samples per group.</p