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The anti-PD-1 immune checkpoint blocker can induce sustained clinical responses in some patients. This drug is used to release the “brakes” on T cells but how it functions in vivo remains incompletely understood. In a study published in Immunity, the Pittet lab at the MGH Center for Systems Biology uncovers that effective antitumor responses to anti-PD-1 therapy requires a subset of tumor-infiltrating dendritic cells, which produce interleukin 12 (IL-12) and apply “gas” to fuel the antitumor reaction. The findings may lead to new treatment strategies that benefit more patients. [Image: KA-POW! A dendritic cell (yellow) interacts with antitumor T cells (blue) to get rid of cancer.]
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Modern oncology relies on molecular assessments of tumor tissue to develop new therapeutic combinations and select optimal treatments for individual patients. Conventional approaches to cellular fluorescence imaging allow for visualization of just 3-4 proteins at a time, limiting the amount of information we can gain from precious patient biopsy samples. In a new study published in Nature Communications, researchers at CSB developed an approach that uses antibody-DNA conjugates to efficiently “cycle” through the detection and quantification of multiple proteins of interest, dramatically increasing the number of pathways/targets that can be imaged from a single biopsy. This technique allows scientists/physicians to directly visualize complex protein signatures in the biopsied cells and has important implications for understanding how drug therapies affect patients' individual tumors.
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White blood cells are our key defenders against infection, however if oversupplied, they may turn against us. Neutrophils are made in the bone marrow where they arise from hematopoietic stem cells. The bone marrow is distributed over many bones in our bodies, and the current thinking implies that the supply of leukocytes distributes evenly throughout the body. In work published in Nature Neuroscience, we describe that the skull marrow assumes a special role in inflammatory diseases of the CNS. Its proximity to the brain leads to a preferential supply of neutrophils. We detected a previously unknown shortcut that neutrophils use on their way from skull marrow cavities towards the central nervous system. Rather than traveling through the general blood circulation, leukocytes produced in skull bone marrow migrate through channels that directly connect the skull marrow with the meninges the brain is wrapped in. The channels exist in mice and humans.
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Automating cellular diagnostics could have far reaching impact in healthcare. Cells - often obtained by aspirations, biopsies, swabs or through body fluids - typically require sophisticated instrumentation and time consuming experts analysis to provide diagnoses. The CSB engineering team has now developed a highly sensitive platform powered by digital imaging and artificial intelligence to automate such painstaking analyses. Moreover this platform is affordable and portable, thus uniquely suited for point-of-care diagnostics in low and middle income countries (LMIC). A recent study published in Nature Biomedical Engineering highlights the first clinical trial for lymphoma diagnostics.
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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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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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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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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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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.
