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Searching for Ways to Prevent Life-Threatening Blood Clots in COVID-19

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At Home with Gary Gibbons

Six months into the coronavirus disease 2019 (COVID-19) pandemic, researchers still have much to learn about the many ways in which COVID-19 can wreak devastation on the human body. Among the many mysteries is exactly how SARS-CoV-2, which is the novel coronavirus that causes COVID-19, triggers the formation of blood clots that can lead to strokes and other life-threatening complications, even in younger people.

Recently, I had a chance to talk with Dr. Gary Gibbons, Director of NIH’s Heart, Lung, and Blood Institute (NHLBI) about what research is being done to tackle this baffling complication of COVID-19. Our conversation took place via videoconference, with him connecting from his home in Washington, D.C., and me linking in from my home just up the road in Maryland. Here’s a condensed transcript of our chat:

Collins: I’m going to start by asking about the SARS-CoV-2-induced blood clotting not only in the lungs, but in other parts of the body. What do we know about the virus that would explain this?

Gibbons: It seems like every few weeks another page gets turned on COVID-19, and we learn even more about how this virus affects the body. Blood clots are one of the startling and, unfortunately, devastating complications that emerged as patients were cared for, particularly in New York City. It became apparent that certain individuals had difficulty getting enough oxygen into their system. The difficulty couldn’t be explained entirely by the extent of the pneumonia affecting the lungs’ ability to exchange oxygen.

It turned out that, in addition to the pneumonia, blood clots in the lungs were compromising oxygenation. But some patients also had clotting, or thrombotic, complications in their veins and arteries in other parts of the body. Quite puzzling. There were episodes of relatively young individuals in their 30s and 40s presenting with strokes related to blood clots affecting the arterial circulation to the brain.

We’re still trying to understand what promotes the clotting. One clue involves the endothelial cells that form the inner lining of our blood vessels. These cells have on their surface a protein called the angiotensin-converting enzyme 2 (ACE2) receptor, and this clue is important for two reasons. One, the virus attaches to the ACE2 receptor, using it as an entry point to infect cells. Two, endothelial-lined blood vessels extend to every organ in the body. Taken together, it seems that some COVID-19 complications relate to the virus attaching to endothelial cells, not only in the lungs, but in the heart and multiple organs.

Collins: So, starting in the respiratory tree, the virus somehow breaks through into a blood vessel and then gets spread around the body. There have been strange reports of people with COVID-19 who may not get really sick, but their toes look frostbitten. Is “COVID toes,” as some people call it, also part of this same syndrome?

Gibbons: We’re still in the early days of learning about this virus. But I think this offers a further clue that the virus not only affects large vessels but small vessels. In fact, clots have been reported at the capillary level, and that’s fairly unusual. It’s suggestive that an interaction is taking place between the platelets and the endothelial surface.

Normally, there’s a tightly regulated balance in the bloodstream between pro-coagulant and anticoagulant proteins to prevent clotting and keep the blood flowing. But when you cut your finger, for example, you get activation for blood clots in the form of a protein mesh. It looks like a fishing net that can help seal the injury. In addition, platelets in the blood stream help to plug the holes in that fishing net and create a real seal of a blood vessel.

Well, imagine it happening in those small vessels, which usually have a non-stick endothelial surface, almost like Teflon, that prevents clotting. Then the virus comes along and tips the balance toward promoting clot formation. This disturbs the Teflon-like property of the endothelial lining and makes it sticky. It’s incredible the tricks this virus has learned by binding onto one of these molecules in the endothelial lining.

Collins: Who are the COVID-19 patients most at risk for this clotting problem?

Gibbons: Unfortunately, it appears right now that older adults are among the most vulnerable. They have a lot of the risks for the formation of these blood clots. What’s notable is these thrombotic complications are also happening to relatively young adults or middle-aged individuals who don’t have a lot of other chronic conditions, or comorbidities, to put them at higher risk for severe disease. Again, it’s suggestive that this virus is doing something that is particular to the coagulation system.

Collins: We’d love to have a way of identifying in advance the people who are most likely to get into trouble with blood clotting. They might be the ones you’d want to start on an intervention, even before you have evidence that things are getting out of control. Do you have any kind of biomarker to tell you which patients might benefit from early intervention?

Gibbons: Biomarkers are being actively studied. What we do know from some earlier observations is that you can assess the balance of clotting and anticlotting factors in the blood by measuring a biomarker called D-dimer. It’s basically a protein fragment, a degradation product, from a prior clot. It tells you a bit about the system’s activity in forming and dissolving clots.
If there’s a lot of D-dimer activity, it suggests a coagulation cascade is jazzed up. In those patients, it’s probably a clue that this is a big trigger in terms of coagulation and thrombosis. So, D-dimer levels could maybe tell us which patients need really aggressive full anticoagulation.

Collins: Have people tried empirically using blood thinners for people who seem to be getting into trouble with this clotting problem?

Gibbons: There’s a paper out of the Mount Sinai in New York City that looked at thousands of patients being treated for COVID-19 [1]. Based on clinical practice and judgments, one of the striking findings is that those who were fully anticoagulated had better survival than those who were not. Now, this was not a randomized, controlled clinical trial, where some were given full anticoagulation and others were not. It was just an observational study that showed an association. But this study indicated indirectly that by giving the blood thinners, changing that thrombotic risk, maybe it’s possible to reduce morbidity and mortality. That’s why we need to do a randomized, controlled clinical trial to see if it can be used to reduce these case fatality rates.

Collins: You and your colleagues got together and came up with a design for such a clinical trial. Tell us about that.

Gibbons: My institute studies the heart, lung, and blood. The virus attacks all three. So, our community has a compelling need to lean in and study COVID-19. Recently, NIH helped to launch a public-private partnership called Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV). As the name spells out, this initiative provides is a clinical platform to generate life-saving treatments as we wait for the development of a vaccine.

Through ACTIV, a protocol is now in the final stages of review for a clinical trial that will involve a network of hospitals and explore the question: is it sufficient to try a low-dose thrombo-prophylactic, or clot preventative, approach versus full anticoagulation? Some think patients ought to have full anticoagulation, but that’s not without risk. So, we want to put that question to the test. As part of that, we’ll also learn more about biomarkers and what could be predictive of individuals getting the greatest benefit.

If we find that fully anticoagulating patients prevents clots, then that’s great. But it begs the question: what happens when patients go home? Is it sufficient to just turn off the drip and let them go their merry way? Should they have a low dose thrombo-prophylactic regimen for a period of time? If so, how long? Or should they be fully anticoagulated with oral anticoagulation for a certain period of time? All these and other questions still remain.

Collins: This can make a huge difference. If you’re admitted to the hospital with COVID-19, that means you’re pretty sick and, based on the numbers that I’ve seen, your chance of dying is about 12 percent if nothing else happens. If we can find something like an anticoagulant that would reduce that risk substantially, we can have a huge impact on reducing deaths from COVID-19. How soon can we get this trial going, Gary?

Gibbons: We have a sense of urgency that clearly this pandemic is taking too many lives and time is of the essence. So, we’ve indeed had a very streamlined process. We’re leveraging the fact that we have clinical trial networks, where regardless of what they were planning to do, it’s all hands on deck. As a result, we’re able to move faster to align with that sense of urgency. We hope that we can be off to a quick launch within the next two to three weeks with the anticoagulation trials.

Collins: This is good because people are waiting on the vaccines, but realistically we won’t know whether the vaccines are working for several more months, and having them available for lots of people will be at the very end of this year or early 2021 at best. Meanwhile, people still are going to be getting sick with COVID-19. We want to be able to have as many therapeutic options as possible to offer to them. And this seems like a pretty exciting one to try and move forward as quickly as possible. You and your colleagues deserve a lot of credit for bringing this to everybody’s attention.

But before we sign off, I have to raise another issue of deep significance. Gary, I think both of us are struggling not only with the impact of COVID-19 on the world, but the profound sorrow, grief, frustration, and anger that surrounds the death of George Floyd. This brings into acute focus the far too numerous other circumstances where African Americans have been mistreated and subjected to tragic outcomes.

This troubling time also shines a light on the health disparities that affect our nation in so many ways. We can see what COVID-19 has done to certain underrepresented groups who have borne an undue share of the burden, and have suffered injustices at the hands of society. It’s been tough for many of us to admit that our country is far from treating everyone equally, but it’s a learning opportunity and a call to redouble our efforts to find solutions.

Gary, you’ve been a wonderful leader in that conversation for a long time. I want to thank you both for what you’re doing scientifically and for your willingness to speak the truth and stand up for what’s right and fair. It’s been great talking to you about all these issues.

Gibbons: Thank you. We appreciate this opportunity to fulfill NIH’s mission of turning scientific discovery into better health for all. If there’s any moment that our nation needs us, this is it.

Reference:

[1] Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. Paranjpe I, Fuster V, Lala A, Russak A, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN. J Am Coll Cardiol. 2020 May 5;S0735-1097(20)35218-9.

Links:

Coronavirus (COVID-19) (NIH)

Rising to the Challenge of COVID-19: The NHLBI Community Response,” Director’s Messages, National Heart, Lung, and Blood Institute/NIH, April 29, 2020.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) (NIH)


The Prime Cellular Targets for the Novel Coronavirus

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Credit: NIH

There’s still a lot to learn about SARS-CoV-2, the novel coronavirus that causes COVID-19. But it has been remarkable and gratifying to watch researchers from around the world pull together and share their time, expertise, and hard-earned data in the urgent quest to control this devastating virus.

That collaborative spirit was on full display in a recent study that characterized the specific human cells that SARS-CoV-2 likely singles out for infection [1]. This information can now be used to study precisely how each cell type interacts with the virus. It might ultimately help to explain why some people are more susceptible to SARS-CoV-2 than others, and how exactly to target the virus with drugs, immunotherapies, and vaccines to prevent or treat infections.

This work was driven by the mostly shuttered labs of Alex K. Shalek, Massachusetts Institute of Technology, Ragon Institute of MGH, MIT, and Harvard, and Broad Institute of MIT and Harvard, Cambridge; and Jose Ordovas-Montanes at Boston Children’s Hospital. In the end, it brought together (if only remotely) dozens of their colleagues in the Human Cell Atlas Lung Biological Network and others across the U.S., Europe, and South Africa.

The project began when Shalek, Ordovas-Montanes, and others read that before infecting human cells, SARS-CoV-2 docks on a protein receptor called angiotensin-converting enzyme 2 (ACE2). This enzyme plays a role in helping the body maintain blood pressure and fluid balance.

The group was intrigued, especially when they also learned about a second enzyme that the virus uses to enter cells. This enzyme goes by the long acronym TMPRSS2, and it gets “tricked” into priming the spike proteins that cover SARS-CoV-2 to attack the cell. It’s the combination of these two proteins that provide a welcome mat for the virus.

Shalek, Ordovas-Montanes, and an international team including graduate students, post-docs, staff scientists, and principal investigators decided to dig a little deeper to find out precisely where in the body one finds cells that express this gene combination. Their curiosity took them to the wealth of data they and others had generated from model organisms and humans, the latter as part of the Human Cell Atlas. This collaborative international project is producing a comprehensive reference map of all human cells. For its first draft, the Human Cell Atlas aims to gather information on at least 10 billion cells.

To gather this information, the project relies, in part, on relatively new capabilities in sequencing the RNA of individual cells. Keep in mind that every cell in the body has essentially the same DNA genome. But different cells use different programs to decide which genes to turn on—expressing those as RNA molecules that can be translated into protein. The single-cell analysis of RNA allows them to characterize the gene expression and activities within each and every unique cell type. Based on what was known about the virus and the symptoms of COVID-19, the team focused their attention on the hundreds of cell types they identified in the lungs, nasal passages, and intestines.

As reported in Cell, by filtering through the data to identify cells that express ACE2 and TMPRSS2, the researchers narrowed the list of cell types in the nasal passages down to the mucus-producing goblet secretory cells. In the lung, evidence for activity of these two genes turned up in cells called type II pneumocytes, which line small air sacs known as alveoli and help to keep them open. In the intestine, it was the absorptive enterocytes, which play an important role in the body’s ability to take in nutrients.

The data also turned up another unexpected and potentially important connection. In these cells of interest, all of which are found in epithelial tissues that cover or line body surfaces, the ACE2 gene appeared to ramp up its activity in concert with other genes known to respond to interferon, a protein that the body makes in response to viral infections.

To dig further in the lab, the researchers treated cultured cells that line airways in the lungs with interferon. And indeed, the treatment increased ACE2 expression.

Earlier studies have suggested that ACE2 helps the lungs to tolerate damage. Completely missed was its connection to the interferon response. The researchers now suspect that’s because it hadn’t been studied in these specific human epithelial cells before.

The discovery suggests that SARS-CoV-2 and potentially other coronaviruses that rely on ACE2 may take advantage of the immune system’s natural defenses. When the body responds to the infection by producing more interferon, that in turn results in production of more ACE2, enhancing the ability of the virus to attach more readily to lung cells. While much more work is needed, the finding indicates that any potential use of interferon as a treatment to fight COVID-19 will require careful monitoring to determine if and when it might help patients.

It’s clear that these new findings, from data that weren’t originally generated with COVID-19 in mind, contained several potentially important new leads. This is another demonstration of the value of basic science. We can also rest assured that, with the outpouring of effort from members of the scientific community around the globe to meet this new challenge, progress along these and many other fronts will continue at a remarkable pace.

Reference:

[1] SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Ziegler, CGK et al. Cell. April 20, 2020.

Links:

Coronaviruses (National Institute of Allergy and Infectious Diseases/NIH)

Human Cell Atlas (Broad Institute, Cambridge, MA)

Shalek Lab (Harvard Medical School and Massachusetts Institute of Technology, Cambridge)

Ordovas-Montanes Lab (Boston Children’s Hospital, MA)

NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences; National Heart, Lung, and Blood Institute


Bringing Needed Structure to COVID-19 Drug Development

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SARS-Cov-2 Molecular Map
Caption: Molecular map showing interaction between the spike protein (gold) of the novel coronavirus and the peptidase domain (blue) of human angiotensin-converting enzyme 2 (ACE2). Credit: Adapted from Yan R., Science, 2020.

With so much information swirling around these days about the coronavirus disease 2019 (COVID-19) pandemic, it would be easy to miss one of the most interesting and significant basic science reports of the past few weeks. It’s a paper published in the journal Science [1] that presents an atomic-scale snapshot showing the 3D structure of the spike protein on the novel coronavirus attached to a human cell surface protein called ACE2, or angiotensin converting enzyme 2. ACE2 is the receptor that the virus uses to gain entry.

What makes this image such a big deal is that it shows—in exquisite detail—how the coronavirus attaches to human cells before infecting them and making people sick. The structural map of this interaction will help guide drug developers, atom by atom, in devising safe and effective ways to treat COVID-19.

This new work, conducted by a team led by Qiang Zhou, Westlake Institute for Advanced Study, Hangzhou, China, took advantage of a high-resolution imaging tool called cryo-electron microscopy (cryo-EM). This approach involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera. When all goes well, cryo-EM can solve the structure of intricate macromolecular complexes in a matter of days, including this one showing the interaction between a viral protein and human protein.

Zhou’s team began by mapping the structure of human ACE2 in a complex with B0AT1, which is a membrane protein that it helps to fold. In the context of this complex, ACE2 is a dimer—a scientific term for a compound composed of two very similar units. Additional mapping revealed how the surface protein of the novel coronavirus interacts with ACE2, indicating how the virus’s two trimeric (3-unit) spike proteins might bind to an ACE2 dimer. After confirmation by further research, these maps may well provide a basis for the design and development of therapeutics that specifically target this critical interaction.

The ACE2 protein resides on the surface of cells in many parts of the human body, including the heart and lungs. The protein is known to play a prominent role in the body’s complex system of regulating blood pressure. In fact, a class of drugs that inhibit ACE and related proteins are frequently prescribed to help control high blood pressure, or hypertension. These ACE inhibitors lower blood pressure by causing blood vessels to relax.

Since the COVID-19 outbreak, many people have wondered whether taking ACE inhibitors would be helpful or detrimental against coronavirus infection. This is of particular concern to doctors whose patients are already taking the medications to control hypertension. Indeed, data from China and elsewhere indicate hypertension is one of several coexisting conditions that have consistently been reported to be more common among people with COVID-19 who develop life-threatening severe acute respiratory syndrome.

In a new report in this week’s New England Journal of Medicine, a team of U.K. and U.S. researchers, partly supported by NIH, examined the use of ACE inhibitors and other angiotensin-receptor blockers (ARBs) in people with COVID-19. The team, led by Scott D. Solomon of Brigham and Women’s Hospital and Harvard Medical School, Boston, found that current evidence in humans is insufficient to support or refute claims that ACE inhibitors or ARBs may be helpful or harmful to individuals with COVID-19.

The researchers concluded that these anti-hypertensive drugs should be continued in people who have or at-risk for COVID-19, stating: “Although additional data may further inform the treatment of high-risk patients … clinicians need to be cognizant of the unintended consequences of prematurely discontinuing proven therapies in response to hypothetical concerns.” [2]

Research is underway to generate needed data on the use of ACE inhibitors and similar drugs in the context of the COVID-19 pandemic, as well as to understand more about the basic mechanisms underlying this rapidly spreading viral disease. This kind of fundamental research isn’t necessarily the stuff that will make headlines, but it likely will prove vital to guiding the design of effective drugs that can help bring this serious global health crisis under control.

References:

[1] Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Science. 27 March 2020. [Epub ahead of publication]

[2] Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. Vaduganathan M, Vardeny O, Michel T, McMurray J, Pfeffer MA, Solomon SD. 30 NEJM. March 2020 [Epub ahead of Publication]

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Transformative High Resolution Cryo-Electron Microscopy (Common Fund/NIH)

Qiang Zhou (Westlake Institute for Advanced Study, Zhejiang Province)

Scott D. Solomon (Brigham and Women’s Hospital, Boston)

NIH Support: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute


Tackling Fibrosis with Synthetic Materials

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April Kloxin
April Kloxin/Credit: Evan Krape, University of Delaware, Newark

When injury strikes a limb or an organ, our bodies usually heal quickly and correctly. But for some people, the healing process doesn’t shut down properly, leading to excess fibrous tissue, scarring, and potentially life-threatening organ damage.

This permanent scarring, known as fibrosis, can occur in almost every tissue of the body, including the heart and lungs. With support from a 2019 NIH Director’s New Innovator Award, April Kloxin is applying her expertise in materials science and bioengineering to build sophisticated fibrosis-in-a-dish models for unraveling this complex process in her lab at the University of Delaware, Newark.

Though Kloxin is interested in all forms of fibrosis, she’s focusing first on the incurable and often-fatal lung condition called idiopathic pulmonary fibrosis (IPF). This condition, characterized by largely unexplained thickening and stiffening of lung tissue, is diagnosed in about 50,000 people each year in the United States.

IPF remains poorly understood, in part because it often is diagnosed when the disease is already well advanced. Kloxin hopes to turn back the clock and start to understand the disease at an earlier stage, when interventions might be more successful. The key is to develop a model that better recapitulates the complexity and irreversibility of the disease process in people.

Building that better model starts with simulating the meshwork of collagen and other proteins in the extracellular matrix (ECM) that undergird every tissue and organ in the body. The ECM’s interactions with our cells are essential in wound healing and, when things go wrong, also in causing fibrosis.

Kloxin will build three-dimensional hydrogels, crosslinked sponge-like networks of polymers, peptides, and proteins, with structures that more accurately capture the biological complexities of human tissues, including the ECMs within fibrous collagen-rich microenvironments. Her synthetic matrices can be triggered with light to lock in place and stiffen. The matrices also will make it possible to culture the lung’s epithelium, or outermost layer of cells, and connective tissue that surrounds it, to study cellular responses as the model shifts from a healthy and flexible to a stiffened, disease-like state.

Kloxin and her team will also integrate into their model system lung cells that have been engineered to fluoresce or light up under a microscope when the wound-healing program activates. Such fluorescent reporters will allow her team to watch for the first time how different cells and their nearby microenvironment respond as the composition of the ECM changes and stiffens. With this system, she’ll also be able to search for small molecules with the ability to turn off excessive wound healing.

The hope is that what’s learned with her New Innovator Award will lead to fresh insights and ultimately new treatments for this mysterious, hard-to-treat condition. But the benefits could be even more wide-ranging. Kloxin thinks that her findings will have implications for the prevention and treatment of other fibrotic diseases as well.

Links:

Idiopathic Pulmonary Fibrosis (National Heart, Lung, and Blood Institute/NIH)

April Kloxin Group (University of Delaware, Newark)

Kloxin Project Information (NIH RePORTER)

NIH Director’s New Innovator Award (Common Fund)

NIH Support: Common Fund; National Heart, Lung, and Blood Institute


Working to Improve Immunotherapy for Lung Cancer

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Lung Cancer Immunotherapy
Credit: Xiaodong Zhu, Fred Hutchinson Cancer Research Center, Seattle

For those who track cancer statistics, this year started off on a positive note with word that lung cancer deaths continue to decline in the United States [1]. While there’s plenty of credit to go around for that encouraging news—and continued reduction in smoking is a big factor—some of this progress likely can be ascribed to a type of immunotherapy, called PD-1 inhibitors. This revolutionary approach has dramatically changed the treatment landscape for the most common type of lung cancer, non-small cell lung cancer (NSCLC).

PD-1 inhibitors, which have only been available for about five years, prime one component of a patient’s own immune system, called T cells, to seek and destroy malignant cells in the lungs. Unfortunately, however, only about 20 percent of people with NSCLC respond to PD-1 inhibitors. So, many researchers, including the team of A. McGarry Houghton, Fred Hutchinson Cancer Research Center, Seattle, are working hard to extend the benefits of immunotherapy to more cancer patients.

The team’s latest paper, published in JCI Insight [2], reveals that one culprit behind a poor response to immunotherapy may be the immune system’s own first responders: neutrophils. Billions of neutrophils circulate throughout the body to track down abnormalities, such as harmful bacteria and malignant cells. They also contact other parts of the immune system, including T cells, if help is needed to eliminate the health threat.

In their study, the Houghton team, led by Julia Kargl, combined several lab techniques to take a rigorous, unbiased look at the immune cell profiles of tumor samples from dozens of NSCLC patients who received PD-1 inhibitors as a frontline treatment. The micrographs above show tumor samples from two of these patients.

In the image on the left, large swaths of T cells (light blue) have infiltrated the cancer cells (white specks). Interestingly, other immune cells, including neutrophils (magenta), are sparse.

In contrast, in the image on the right, T cells (light blue) are sparse. Instead, the tumor teems with other types of immune cells, including macrophages (red), two types of monocytes (yellow, green), and, most significantly, lots of neutrophils (magenta). These cells arise from myeloid progenitor cells in the bone marrow, while T cells arise from the marrow’s lymphoid progenitor cell.

Though the immune profiles of some tumor samples were tough to classify, the researchers found that most fit neatly into two subgroups: tumors showing active levels of T cell infiltration (like the image on the left) or those with large numbers of myeloid immune cells, especially neutrophils (like the image on the right). This dichotomy then served as a reliable predictor of treatment outcome. In the tumor samples with majority T cells, the PD-1 inhibitor worked to varying degrees. But in the tumor samples with predominantly neutrophil infiltration, the treatment failed.

Houghton’s team has previously found that many cancers, including NSCLC, actively recruit neutrophils, turning them into zombie-like helpers that falsely signal other immune cells, like T cells, to stay away. Based on this information, Houghton and colleagues used a mouse model of lung cancer to explore a possible way to increase the success rate of PD-1 immunotherapy.

In their mouse experiments, the researchers found that when PD-1 was combined with an existing drug that inhibits neutrophils, lung tumors infiltrated with neutrophils were converted into tumors infiltrated by T cells. The tumors treated with the combination treatment also expressed genes associated with an active immunotherapy response.

This year, January brought encouraging news about decreasing deaths from lung cancer. But with ongoing basic research, like this study, to tease out the mechanisms underlying the success and failure of immunotherapy, future months may bring even better news.

References:

[1] Cancer statistics, 2020. Siegel RL, Miller KD, Jemal A. CA Cancer J Clin. 2020 Jan;70(1):7-30.

[2] Neutrophil content predicts lymphocyte depletion and anti-PD1 treatment failure in NSCLC. Kargl J, Zhu X, Zhang H, Yang GHY, Friesen TJ, Shipley M, Maeda DY, Zebala JA, McKay-Fleisch J, Meredith G, Mashadi-Hossein A, Baik C, Pierce RH, Redman MW, Thompson JC, Albelda SM, Bolouri H, Houghton AM. JCI Insight. 2019 Dec 19;4(24).

[3] Neutrophils dominate the immune cell composition in non-small cell lung cancer. Kargl J, Busch SE, Yang GH, Kim KH, Hanke ML, Metz HE, Hubbard JJ, Lee SM, Madtes DK, McIntosh MW, Houghton AM. Nat Commun. 2017 Feb 1;8:14381.

Links:

Non-Small Cell Lung Cancer Treatment (PDQ®)–Patient Version (National Cancer Institute/NIH)

Spotlight on McGarry Houghton (Fred Hutchinson Cancer Research Center, Seattle)

Houghton Lab (Fred Hutchinson Cancer Research Center)

NIH Support: National Cancer Institute


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