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.
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.
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.
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.
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.
Iron gives blood its red color. The metal is essential to life, but it can be toxic because of its oxidative properties. Remarkably, we receive relatively little of our daily iron needs through diet. By far the majority of the iron we need is recycled. According to current thinking, as red blood cells age, large phagocytes residing in the spleen capture them, digest the cell structures, and recycle iron. A new paper from CSB published in Nature Medicine shows that most red blood cell disposal actually occurs in the liver, especially when demands for disposal increase (as they do in many physiologic and pathophysiologic situations). Moreover, specialized white blood cells consume old red blood cells in the circulation before migrating to the liver to shuttle iron for storage and new red blood cell production. The process buffers against dangerous fluctuations in iron availability, keeping the body in balance.
Quintuple-target RNAi: hitting five targets at once
Vascular endothelial cells express five adhesion molecules to recruit leukocytes from the blood stream: E- and P-selectin, ICAM-1 and -2, and VCAM-1. In atherosclerosis, activated endothelial cells express high levels of these signals, thus expanding the number of neutrophils and monocytes that migrate from blood into a growing plaque. After myocardial infarction, the adhesion molecule expression increases even further due to higher autonomic nervous activity. A collaborating team of groups at MIT and MGH now used a new class of nanoparticles with high avidity to endothelial cells to decrease endothelial cell adhesion molecule expression. The polymeric nanoparticles made of low-molecular-weight polyamines and lipids were loaded with 5 distinct siRNAs silencing the expression of all adhesion molecules. Multiple gene silencing was enabled by exquisite silencing efficiency after nanoparticle delivery. Hitting five targets at once, the therapy reduced recruitment of leukocytes to atherosclerotic plaques in mice, dampening vascular wall inflammation and making plaques smaller. Furthermore, RNAi decreased migration of leukocytes into infarcted myocardium, improving the recovery after ischemia. Such a strategy may help to prevent reinfarction and heart failure in high-risk patients with acute MI.
Rapid and efficient diagnosis of bacterial infection is critical in combating infections, esp. in the hospital setting where drug resistnace to antibiotics is on the rise. CSB investigators have developed a new device to shorten the diagnosis of bacterial infection to less than 2 hours. The “PAD” system (short for polarization diagnostics) is a combination of optical read-outs of genetic bacterial information and can ultimately performed in a physician’s office at low cost.
Macrophages are mostly viewed as tumor-promoting cells. They can infiltrate solid tumors in high numbers, and their presence at the tumor site is often associated with decreased patient survival. However, much less is known about macrophages located outside the tumor stroma. Mikael Pittet and colleagues now show that a population of lymph node macrophages, called subcapsular sinus (SCS) macrophages, unexpectedly protects against melanoma. The study was published in Science on March 17, 2016
Novel immune checkpoint blockade therapies can be extraordinarily effective but may benefit only the minority of patients whose tumors are pre-infiltrated by antitumor immune cells called CD8+ T cells. In a study published in Immunity, the Pittet lab at MGH Center for Systems Biology reports that rationally selected immunogenic chemotherapy can convert tumor microenvironments lacking T cells into ones displaying antitumor T cell immunity. This process makes unresponsive tumors sensitive to immune checkpoint blockade therapies and consequently raises hope to feasibly expand the proportion of human cancers responding to these therapies.
Nanoparticles promise to deliver toxic chemotherapeutics more safely and efficiently to solid tumors, but clinical responses to such treatments have been mixed: some patients respond extremely well while others do not. Using advanced imaging techniques, researchers at CSB have discovered a way to repurpose FDA-approved magnetic nanoparticles for predicting how effectively nanomedicines can accumulate in tumors. Published in Science Translational Medicine, this “companion diagnostic" approach suggests that clinical imaging can be used to select patients most likely to benefit from the most advanced nanomedicine treatments.
Macrophages act as drug delivery depots of nanomedicines
Solid tumors often contain large numbers of immune cells including macrophages that feed cancer growth and metastasis. CSB researchers discovered that these tumor associated macrophages can be co-opted by nanomaterials to serve as drug depots, gradually delivering chemotherapy to neighboring cancer cells. Driven by new intravital imaging technology and published in Nature Communications, this research presents a new paradigm for therapeutic design and for selecting patients into clinical trials.
Bone marrow stem cells are alerted to heart attack.
The white blood count is one of the most frequently ordered medical tests, reflecting its clinical value. In patients with heart disease, leukocytosis closely correlates with survival. We increasingly understand why: inflammatory monocytes and macrophages, when overproduced, damage the arterial wall and vital organs such as the heart after myocardial infarction. We have surprisingly limited understanding of mechanisms leading to increased leukocyte count in cardiovascular patients. Blood cells, including inflammatory monocytes, are made in the bone marrow and ultimately derive from pluripotent hematopoietic stem cells. Until now it was unknown which bone marrow cells expand in acute myocardial infarction. Recent work published in Cell Stem Cell identified a subpopulation of progenitors as the most upstream activation point after MI. The surface marker CCR2 identifies, in mice and in humans, the cells that sit almost at the very top of the hematopoietic tree as particularly responsive to an injury of the heart. The myeloid translocation gene 16 regulates the emergence of these highly active stem cells, and may provide a therapeutic target to dampen leukocyte production that could otherwise jeopardize resolution of inflammatory activity in cardiovascular organs. The interdisciplinary work united cardiovascular, immunology, imaging and hematology scientists in a collaborative effort to tease out cross talk between the injured heart and blood stem cells.
With their ubiquitous presence and superb computation power, smartphones now bring unprecedented opportunities to realize mobile healthcare. Reported in PNAS, CSB researchers have developed a new smartphone-based system, D3 (digital diffraction diagnosis), for on-the-spot molecular detection. This system, complete with a custom App, was used for cervical cancer screen and diagnosing aggressive lymphomas, prevalent cancers in low and middle-income countries.
The complication of an infection known as sepsis (or “blood poisoning”) is extremely dangerous, claiming up to half a million lives in the United States every year. A study from the Swirski lab has shown that a growth factor called interleukin-3 (IL-3) amplifies inflammation in sepsis and potentiates septic shock, the most severe form of sepsis. The authors show that IL-3 induces the emergency production of inflammatory monocytes and neutrophils, which are sources of the hallmark cytokines that comprise a lethal cytokine storm. A subset of B-1 B cells, discovered in the Swirski lab and named IRA B cells, are abundant sources of IL-3 in sepsis. Patients diagnosed with sepsis with high IL-3 in their blood die more often than those containing low IL-3.
When our drugs don’t work.
Eribulin was developed as a potent anticancer agent, but it fails in many patients for unknown reasons. In a recent study, CSB researchers used microscopic imaging in tumors to show that resistance is primarily due to MDR1-mediated drug efflux. It was discovered that a new nano-encapsulated MDR1 inhibitor was able to restore drug efficacy. These studies show that in vivo imaging is a powerful strategy for elucidating mechanisms of drug resistance in heterogeneous tumors and for evaluating strategies to overcome this resistance.
For decades, doctors knew that chronic stress is bad for you. Atherosclerosis has been nicknamed a “manager’s disease” for this reason. Previously, we thought this is because of heightened blood pressure, and its direct actions on the blood vessel wall. The study by Heidt and Sager found that psychosocial stress activates bone marrow stem cells, which in turn triggers overproduction of inflammatory leukocytes, including neutrophils and monocytes. These leukocytes are more numerous in blood and accumulate in atherosclerotic lesions, putting the individual at higher risk for myocardial infarction and stroke.
Tiny holes enable big measurements
A new technology developed at CSB allows profiling of small subcellular structures such as exosomes. The technology uses tiny gold grids studded with nanoholes in array format. Each of the holes has been modified with different antibodies. Biomarkers interacting with these tiny nano holes change the light properties (nano-plasmons), an effect which can optically detected. This technology (”nPLEX”) will allow high-throughput analysis of a number of clinically important biomarkers.
Extracting maximal information from minimal, easily acquired samples is the holy grail for patient monitoring in clinical trials. Until now, invasive or expensive procedures have been the only means of gaining accurate information regarding disease status and treatment response. Now, a new technology developed at the CSB, published in Science Translational Medicine holds promise for revolutionizing clinical monitoring by allowing vast amounts of proteomic information to be obtained from minute samples.
Buildup of cancer-containing fluid in the abdomen (ascites) is a common occurrence suffered by many patients with advanced malignancies. Currently, examining these cells is only useful for upfront diagnoses. Subsequent ascites collected is often discarded. Researchers have developed and tested a novel microfluidic chip, reported in PNAS, to selectively detect ascites tumor cells and enable further testing. This approach seeks to repurpose ascites for serial pharmacodynamic readouts.
According to a recent study by CSB researchers, the primary driver of atherosclerotic plaque growth is local proliferation of plaque-resident inflammatory cells. This finding not only challenges previous assumptions that plaque growth is the exclusive result of cell recruitment from the blood, but now raises hope for the future development of targeted atherosclerotic treatment. Findings are reported in Nature Medicine.
Researchers have developed a quick and sensitive method for identifying and characterizing infectious bacteria in patient samples. The genetic test uses specially designed DNA probes that seek out and magnetically label regions of bacterial RNA. Reported in Nature Nanotechnology, this diagnostic technique is powerful enough to detect and differentiate single bacteria in under 2 hours. It could thus catch infection early and guide treatment decisions.
A new cost-efficient, portable diagnostic test that can detect the presence of drug-sensitive and drug-resistant tubercular bacteria directly in patient sputum has been developed by a collaborative group at the CSB. The innovative diagnostic device, described in Nature Communications, uses microfluidic technology with nuclear magnetic resonance to detect magnetically tagged TB-related genetic material in unprocessed samples.
A novel diagnostic platform has been shown capable of detecting minuscule particles shed by cells, known as microvesicles, in a drop of blood. In a groundbreaking study, published in Nature Medicine, investigators at the Center for Systems Biology (CSB) demonstrate that by using nanotechnology together with nuclear magnetic resonance (NMR), microvesicles shed by brain cancer cells can be reliably detected in human blood samples.
Imaging individual cells in a live beating heart has been nearly impossible. Yet, this would offer unprecedented opportunities to better understand heart diseases. A new imaging method – reported in the October issue of Nature Communications – and developed by researchers at the Center for System Biology now allows single cell resolution imaging in cardiovascular research.
Researchers have developed a novel microchip that can rapidly scan through the enormous number of cells in a blood sample to find very rare circulating tumor cells. Using a combination of microelectronics, microfluidics, and nanotechnology, this new system, described in the July issue of Science Translational Medicine, now has the potential for rapid and accurate on-the-spot cancer diagnosis and treatment monitoring. more…
New research at the Center for Systems Biology (CSB) has shown that heart attacks are not just a “plumbing” problem in the arteries but a ‘whole system’ condition, resulting in widespread inflammation and a predisposition for a secondary attack. more…
The genetic abnormality that causes blood cells to deform and clog vessels in sickle cell disease results in wide symptom variability across patients. Until now, there has been no way to distinguish patients with severe from patients with mild disease. A novel technique, however, has shown promise in differentiating patients based on the rate at which their blood stops flowing under low oxygen. more…
Sepsis is a life-threatening condition characterized by whole-body inflammation to overwhelming infection. Over the last thirty years, its incidence has risen, a fact that serves to highlight our continuing poor understanding of this complex inflammatory state. Recently, however, a newly discovered cell type known as “innate response activator” has been found to protect against sepsis. This discovery will likely provide insight into the development of sepsis and potentially lead to new avenues for therapeutic intervention. more…
By manipulating the molecular navigation system used by inflammatory immune cells to reach sites of tissue damage, researchers at the Center for Systems Biology may have struck upon an effective novel anti-inflammatory treatment. Given that inflammation is an exacerbator of almost all major diseases, this therapy could potentially have wide-spread benefit. more…
A new imaging probe developed by researchers at the Center for Systems Biology can detect acute endocarditis, a rapidly progressing infection of the heart valves. This imaging agent binds tightly to a product released by the most deadly cause of the infection-Staphylococcus aureus-rendering it visible by both optical and PET imaging. Ultimately, the agent could be used to rapidly diagnose, and thus treat, this potentially fatal condition. more…
While the spleen has long held a reputation for redundancy, recent research has now shown that quite the opposite is true. The spleen, in fact, appears to play an important role in the repair of tissue. Mikael Pittet, one of the four lead investigators responsible for this finding, discusses this work and its possible implications. more…
Finding new uses for already FDA approved drugs is a speedy way of translating new biological discoveries into patient benefit. Using a novel catheter-based imaging system, the fluorescent dye Indocyanine green has been shown capable of highlighting the culprits responsible for strokes and heart attacks, namely inflamed arterial plaques. Reliable detection of these plaques could revolutionize cardiovascular diagnosis and on-the-spot treatment. more…
In today’s fast paced world, waiting for anything is often frustrating and stressful. But few delays can be worse than that following a diagnostic blood test or biopsy, where results can take days to come back. Recently, a new portable device, known as DMR has been shown capable of on the spot cancer diagnosis. more…