Primary Murine CD4⁺ T Cells Fail to Acquire the Ability to Produce Effector Cytokines When Active Ras Is Present during Th1/Th2 Differentiation

Constitutive Ras signaling has been shown to augment IL-2 production, reverse anergy, and functionally replace many aspects of CD28 co-stimulation in CD4+ T cells. These data raise the possibility that introduction of active Ras into primary T cells might result in improved functionality in pathologic situations of T cell dysfunction, such as cancer or chronic viral infection. To test the biologic effects of active Ras in primary T cells, CD4+ T cells from Coxsackie-Adenovirus Receptor Transgenic mice were transduced with an adenovirus encoding active Ras. As expected, active Ras augmented IL-2 production in naive CD4+ T cells. However, when cells were cultured for 4 days under conditions to promote effector cell differentiation, active Ras inhibited the ability of CD4+ T cells to acquire a Th1 or Th2 effector cytokine profile. This differentiation defect was not due to deficient STAT4 or STAT6 activation by IL-12 or IL-4, respectively, nor was it associated with deficient induction of T-bet and GATA-3 expression. Impaired effector cytokine production in active Ras-transduced cells was associated with deficient demethylation of the IL-4 gene locus. Our results indicate that, despite augmenting acute activation of naïve T cells, constitutive Ras signaling inhibits the ability of CD4+ T cells to properly differentiate into Th1/Th2 effector cytokine-producing cells, in part by interfering with epigenetic modification of effector gene loci. Alternative strategies to potentiate Ras pathway signaling in T cells in a more regulated fashion should be considered as a therapeutic approach to improve immune responses in vivo.</p

Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment

The molecular identification of tumor antigens initially catalyzed substantial enthusiasm for the development of tumor antigen-based vaccines for the treatment of cancer. However, numerous vaccine approaches in melanoma and other cancers have yielded a low rate of clinical response, despite frequent induction of specific T cells as detected in the peripheral blood. This observation has prompted several investigators to begin interrogating the tumor microenvironment for biologic correlates to tumor response versus resistance. Evidence is beginning to emerge suggesting that distinct subsets of tumors may exist that reflect distinct categories of immune escape. Lack of chemokine-mediated trafficking, poor innate immune cell activation, and the presence of specific immune suppressive mechanisms can be found to characterize subsets of tumors. A non-inflamed tumor phenotype may predict for resistance to cancer vaccines, suggesting a possible predictive biomarker and patient enrichment strategy. But in addition, characterization of these subsets may pave the way for catering therapeutic interventions toward the biologic features of the tumor in individual patients.Fil: Gajewski, Thomas F. . University Of Chicago; Estados UnidosFil: Fuertes, Mercedes Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. University Of Chicago; Estados UnidosFil: Spaapen, Robbert . University Of Chicago; Estados UnidosFil: Zheng, Yan . University Of Chicago; Estados UnidosFil: Kline, Justin . University Of Chicago; Estados Unido

Review of the 25th annual scientific meeting of the International Society for Biological Therapy of Cancer

Led by key opinion leaders in the field, the 25th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc, recently renamed the Society for Immunotherapy of Cancer, SITC) provided a scientific platform for ~500 attendees to exchange cutting-edge information on basic, clinical, and translational research in cancer immunology and immunotherapy. The meeting included keynote addresses on checkpoint blockade in cancer therapy and recent advances in therapeutic vaccination against cancer induced by Human Papilloma Virus 16. Participants from 29 countries interacted through oral presentations, panel discussions, and posters on topics that included dendritic cells and cancer, targeted therapeutics and immunotherapy, innate/adaptive immune interplay in cancer, clinical trial endpoints, vaccine combinations, countering negative regulation, immune cell trafficking to tumor microenvironment, and adoptive T cell transfer. In addition to the 50 oral presentations and >180 posters on these topics, a new SITC/iSBTc initiative to create evidence-based Cancer Immunotherapy Guidelines was announced. The SITC/iSBTc Biomarkers Taskforce announced the release of recommendations on immunotherapy biomarkers and a highly successful symposium on Immuno-Oncology Biomarkers that took place on the campus of the National Institutes of Health (NIH) immediately prior to the Annual Meeting. At the Annual Meeting, the NIH took the opportunity to publicly announce the award of the U01 grant that will fund the Cancer Immunotherapy Trials Network (CITN). In summary, the Annual Meeting gathered clinicians and scientists from academia, industry, and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy

Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and “perceived” business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace

B7DC/PDL2 Promotes Tumor Immunity by a PD-1–independent Mechanism

B7H1 (PDL1) and B7DC (PDL2) are two new members of the B7 family that can interact with PD-1, a putative negative regulator for immune function. Recent studies have provided evidence for inhibitory functions of both members via PD-1. Meanwhile, compelling evidence exists for costimulatory function of both members. Here we demonstrate that expression of B7DC on the tumor cells promotes CD8 T cell–mediated rejection of tumor cells, at both the induction and effector phase of antitumor immunity. Moreover, B7DC binds to PD-1(−/−) cells and enhances T cell killing in a PD-1–independent mechanism. Our results demonstrate a novel pathway for B7DC to promote tumor immunity and may reconcile the apparently contradictory findings on the function of B7DC

Low-temperature transport in highly boron-doped nanocrystalline diamond

International audienceWe studied the transport properties of highly boron-doped nanocrystalline diamond thin films at temperatures down to 50 mK. The system undergoes a doping-induced metal-insulator transition with an interplay between intergranular conductance g and intragranular conductance g0, as expected for a granular system. The conduction mechanism in the case of the low-conductivity films close to the metal-insulator transition has a temperature dependence similar to Efros-Shklovskii type of hopping. On the metallic side of the transition, in the normal state, a logarithmic temperature dependence of the conductivity is observed, as expected for a metallic granular system. Metallic samples far away from the transition show similarities to heavily borondoped single-crystal diamond. Close to the transition, the behavior is richer. Global phase coherence leads in both cases to superconductivity also checked by ac susceptibility , but a peak in the low-temperature magnetoresistance measurements occurs for samples close to the transition. Corrections to the conductance according to superconducting fluctuations account for this negative magnetoresistance

Improving quality indicator report cards through Bayesian modeling

<p>Abstract</p> <p>Background</p> <p>The National Database for Nursing Quality Indicators^®(NDNQI^®) was established in 1998 to assist hospitals in monitoring indicators of nursing quality (eg, falls and pressure ulcers). Hospitals participating in NDNQI transmit data from nursing units to an NDNQI data repository. Data are summarized and published in reports that allow participating facilities to compare the results for their units with those from other units across the nation. A disadvantage of this reporting scheme is that the sampling variability is not explicit. For example, suppose a small nursing unit that has 2 out of 10 (rate of 20%) patients with pressure ulcers. Should the nursing unit immediately undertake a quality improvement plan because of the rate difference from the national average (7%)?</p> <p>Methods</p> <p>In this paper, we propose approximating 95% credible intervals (CrIs) for unit-level data using statistical models that account for the variability in unit rates for report cards.</p> <p>Results</p> <p>Bayesian CrIs communicate the level of uncertainty of estimates more clearly to decision makers than other significance tests.</p> <p>Conclusion</p> <p>A benefit of this approach is that nursing units would be better able to distinguish problematic or beneficial trends from fluctuations likely due to chance.</p

Restoration of a Multi-Functional Landscape: Mill Creek After Dam Removal

Mill Creek has been dammed at the Village of Dexter, Michigan, since the 1820s. The Village‘s relationship with Mill Creek has changed from one based primarily on power for saw and grist mills (economic growth) in the 1800s to one based on a free-flowing stream after the dam‘s removal in 2008. Our recommendations can help the Village of Dexter achieve its ecological goals for Mill Creek Park, improve the watershed‘s health and integrity, improve interpretive and educational experiences, and develop a richer, more diverse relationship between the Village and Mill Creek. Key watershed recommendations are: 1) conduct local restoration/enhancement projects such that they contribute to the watershed‘s ecological functions and processes, 2) reduce the height and angle of artificially high streambanks, 3) reduce erosion around stormwater outfalls, 4) move stormwater from pipes to bioswales, 5) adopt or revise ordinances to protect riparian and wetland areas, to encourage low impact development, and to prevent use of invasive plants in landscaping, 6) remove invasive plant species, 7) move proposed paved trail more than 25 feet from streambanks, 8) reestablish natural disturbances (fire and flooding), and 9) improve safety in the Outdoor Education Area (OEA) by repairing erosion that threatens walkways, removing poison ivy, dead-standing trees and dangerous debris near the trails, and repairing boardwalks and walkways. Key recommendations to facilitate effective relationships between people and Mill Creek are: 1) use this report‘s OEA plant identification guide, 2) establish either a point person or a core group of teachers to manage and effectively use the OEA for education, 3) pursue professional development opportunities for schoolteachers, 4) adopt, pilot test, and measure the effectiveness of the interpretive signs produced by this report, 5) recruit a volunteer program coordinator to plan volunteer activities and schedules, outreach, and supervise workdays, 6) use this report‘s suggested tools and strategies for volunteers, and 7) recruit volunteers from a variety of businesses, civic groups, and organizations.Master of ScienceNatural Resources and EnvironmentUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/69246/1/Restoration of a Multi-Functional Landscape Mill Creek after Dam Removal.pd

Phase 2 study of RO4929097, a gamma‐secretase inhibitor, in metastatic melanoma: SWOG 0933

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110565/1/cncr29055.pd

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