Center for Systems Biology

Research Highlights (more...)

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  Re-educating Tumors

  Tumor-associated macrophages (TAM) are abundant in many cancers and often display an immune-suppressive phenotype that promotes tumor growth and resistance to treatment. Researchers at CSB have now developed a TAM targeted nanoparticle loaded with a toll-like receptor agonist which re-programs TAMs to support the immune-system’s fight against cancer. As a monotherapy, administration of the drug-loaded nanoparticle led to efficient drug delivery to TAMs, re-programming of TAMs to an immune-supportive phenotype, and controlled tumor growth. Importantly, the strategy worked synergistically in combination with checkpoint therapy (anti-PD1), dramatically improving response rates even in tumors resistant to treatment by anti-PD1 alone. These findings demonstrate the ability of rationally engineered drug–nanoparticle combinations to efficiently modulate TAMs to better sensitize the tumor microenvironment to standard checkpoint therapies.

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  Bones and Neutrophils Control Lung Cancer

  Tumors are often infiltrated by diverse immune cell types, some of which remain largely unexplored. In a study published in Science, the Pittet lab at the MGH Center for Systems Biology uncovers a new type of neutrophil that promotes lung cancer. The production of these neutrophils involves an unexpected remote crosstalk between tumors and bones: lung tumors remotely activate osteoblasts; in turn, those bone cells shape immunity by supplying tumors with cancer-promoting neutrophils. The findings open new avenues for cancer immunotherapy. _{(Image from Wikipedia)}

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  Immune cells attend a heart attack masquerade

  Hearts attacks, result from occlusion of coronary arteries, which starves heart muscle cells of oxygen-rich blood and causes them to die. Immune cells respond by entering the dead tissue, clearing cell debris, and stabilizing the heart wall via fibrosis and repair. In their Nature Medicine report, CSB investigators describe the surprising finding that dying cell DNA mimics a virus, which causes immune cells to turn on antiviral programs after a heart attack even though there is no viral infection.

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  Keychain detector catches food allergens before it’s too late

  More than 50 million Americans display food reactions. Each year there are an estimated over 20,000 food allergy-related emergency department visits in the United States, including 90,000 cases of anaphylaxis. The best way to manage food allergy is to avoid products that contain allergen. But avoidance isn't always possible because food can be mislabeled or cross-contaminated.

  Meet iEAT (integrated Exogenous Antigen Testing) a $40 portable allergen-detection system that consists of a disposable kit to extract allergens from food and an electronic keychain analyzer for allergen detection. In less than 10 minutes, the iEAT completes food analyses and sends the results to a cloud server. The prototype was used to detect five model allergens from wheat, peanuts, hazelnuts, milk and egg white. Testing on food items from local restaurants revealed unexpected findings such as gluten in “gluten-free” dishes and egg protein in beer. The technology is being expanded to detect additional allergens, pesticides and environmental hormones.

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  What does a catalytic converter have to do with drugs?

  A lot, it turns out. Catalytic converters in our cars convert toxic gas emissions into into acceptable ones. A key element is the metal palladium, which catalyses the oxidation of pollutants like carbon monoxide to carbon dioxide. In a recent article in Nature Communications, researchers at CSB have developed a medical version of nano-palladium to enable chemistry to take place inside cells in our body. The discovery allows the administration of harmless prodrugs, which then get specifically activated at sites of cancer.

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  A new trick for macrophages

  Macrophages, immune cells in our body, have a long to-do list. They defend us from bacteria, are essential in wound healing, keep the heart beating and perform other vital tasks. In a new twist, these cells are now shown to dramatically accumulate on the outside of cancer microvessels following radiation therapy. There, they elicit dynamic and focally localized bursts of capillary leaks. This in turn enhances drug delivery, especially of nanomaterials. These new insights have implications for the design of next-generation tumor targeted nanomaterials and clinical trials for adjuvant strategies.

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  A signature achievement

  Pancreatic ductal adenocarcinoma is one of the deadliest types of tumors, in part because it is usually detected at a late stage. To facilitate the diagnosis of this tumor, researchers at CSB have developed a multiplexed nanoplasmonic assay to analyze extracellular vesicles in blood of patients. While some blood biomarkers have previously been proposed, none of them have proven sufficiently accurate in clinical practice. We have now identified a new five-marker signature that yielded the most accurate diagnosis in a large cohort of patient samples.

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  Spotlight (literally) on immunotherapy

  Immunotherapy and especially immune checkpoint blockers (ICBs) are revolutionizing how we treat many cancers. Designed to activate the immune system, these drugs can be extraordinarily effective in some patients. But progress has been slowed by our limited understanding of why ICBs work well in some cancers and patients but not in others. Now, Mikael Pittet and colleagues have used molecular imaging to track ICBs in real time and at high resolution within tumors. Their study, published in Science Translational Medicine, uncovers a previously undiscovered mechanism of treatment resistance, which can be overcome with additional chemical modifications.

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  Cardiac macrophages charging ahead

  While we knew for a while that the healthy heart contains tissue resident macrophages, these cells’ organ specific functions were unknown. Triggered by a serendipitous finding of ECG abnormalities during a cardiac MRI scan of a mouse after macrophage ablation, a CSB team of investigators now describes previously unknown electrical properties of macrophages. When coupled to myocytes via gap junctions, macrophages depolarize in sync with conducting cells. In a sink-source relationship, electric current flows back and forth between macrophages and cardiomyocytes. Macrophages influence conduction through the atrioventricular node, the electrical connection between the heart’s chambers. When macrophages are manipulated, the flow of electricity slows down, and may even cease altogether. Such a condition requires pacemaker treatment in humans. These surprising findings, published in Cell, jolt the field of electrophysiology and may lead to new therapeutic opportunities for patients with cardiac arrhythmias. The collaborative effort was spearheaded by teams at MGH but also involved investigators at the BWH and in Freiburg, Germany.

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  Tiny nanoparticles hunt for macrophages

  Macrophages are white blood cells that can turn against us in atherosclerosis. Instead of cleaning up tissue as usual, they attack the arterial wall and destroy its architecture. The resulting stoppage of blood flow causes myocardial infarction and stroke. An entire field of research focuses on understanding these cells, and how to stop them from becoming turn coats. Until now, it was not even possible to detect them reliably in patients. In a recent Nature Communications report, a modified polyglucose nanoparticle (¹⁸F-Macroflor) was developed for imaging macrophages by PET. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. This work marks an important step towards a clinical tool to non-invasively monitor macrophage biology in patients. Such an imaging tool can then be used to spot danger spots in several diseases, and test new macrophage-targeted therapeutics while directly watching the cells.

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