Posted on by Dr. Francis Collins
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 . 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 , 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.
 Cancer statistics, 2020. Siegel RL, Miller KD, Jemal A. CA Cancer J Clin. 2020 Jan;70(1):7-30.
 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).
 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.
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
Posted on by Dr. Francis Collins
Most of our immune cells circulate throughout the bloodstream to serve as a roving security force against infection. But some immune cells don’t travel much at all and instead safeguard a specific organ or tissue. That’s what you are seeing in this electron micrograph of a type of scavenging macrophage, called a Kupffer cell (green), which resides exclusively in the liver (brown).
Normally, Kupffer cells appear in the liver during the early stages of mammalian development and stay put throughout life to protect liver cells, clean up old red blood cells, and regulate iron levels. But in their experimental system, Christopher Glass and his colleagues from University of California, San Diego, removed all original Kupffer cells from a young mouse to see if this would allow signals from the liver that encourage the development of new Kupffer cells.
The NIH-funded researchers succeeded in setting up the right conditions to spur a heavy influx of circulating precursor immune cells, called monocytes, into the liver, and then prompted those monocytes to turn into the replacement Kupffer cells. In a recent study in the journal Immunity, the team details the specific genomic changes required for the monocytes to differentiate into Kupffer cells . This information will help advance the study of Kupffer cells and their role in many liver diseases, including nonalcoholic steatohepatitis (NASH), which affects an estimated 3 to 12 percent of U.S. adults .
The new work also has broad implications for immunology research because it provides additional evidence that circulating monocytes contain genomic instructions that, when activated in the right way by nearby cells or other factors, can prompt the monocytes to develop into various, specialized types of scavenging macrophages. For example, in the mouse system, Glass’s team found that the endothelial cells lining the liver’s blood vessels, which is where Kupffer cells hang out, emit biochemical distress signals when their immune neighbors disappear.
While more details need to be worked out, this study is another excellent example of how basic research, including the ability to query single cells about their gene expression programs, is generating fundamental knowledge about the nature and behavior of living systems. Such knowledge is opening new possibilities to more precise ways of treating and preventing diseases all throughout the body, including those involving Kupffer cells and the liver.
 Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity. Sakai M, Troutman TD, Seidman JS, Ouyang Z, Spann NJ, Abe Y, Ego KM, Bruni CM, Deng Z, Schlachetzki JCM, Nott A, Bennett H, Chang J, Vu BT, Pasillas MP, Link VM, Texari L, Heinz S, Thompson BM, McDonald JG, Geissmann F3, Glass CK. Immunity. 2019 Oct 15;51(4):655-670.
 Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Spengler EK, Loomba R. Mayo Clinic Proceedings. 2015;90(9):1233–1246.
Liver Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Glass Laboratory (University of California, San Diego)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Cancer Institute
Posted on by Dr. Francis Collins
There are nearly 7,000 rare diseases, some of which affect just a few dozen people. Yet, if one considers all these conditions together, about 30 million people in the United States have rare diseases. On this Rare Disease Day, I’d like to challenge each of you to think about how we can raise the visibility of individuals living with rare diseases, as well as the researchers working hard to help them.
I’d like to introduce you to Harper Spero, who is using her rare gift of storytelling to share the experiences of people with a wide variety of conditions that she likes to call “invisible illnesses.” Through her podcast series, called Made Visible, this 34-year-old New York City native is among the many people helping to spread the word that rare diseases are not rare.
Spero knows what it’s like to live with a rare disease. Shortly after she was born, it became clear that she was unusually prone to infections. But doctors had a hard time figuring out what exactly was wrong with this little girl. Finally, at the age of 10, Spero was diagnosed with Hyper-Immunoglobulin E Syndrome (HIES), also known as Job’s syndrome. There currently is no cure for this rare genetic disease, which impairs the immune system and affects multiple parts of the body. But Spero is determined to live a normal life despite her chronic “invisible illness.”
Spero also knows what it’s like to take part in biomedical research. Seven years ago, she came to the NIH Clinical Center here in Bethesda, MD, seeking help for a large cyst in her right lung. It marked the beginning of a positive partnership with a Job’s syndrome research team led by two of NIH’s many dedicated physician-scientists, Alexandra Freeman and Steven Holland. Not only did the NIH researchers work with Spero to figure out the best ways of managing her symptoms, they are using what they’ve learned from her and about 175 other Job’s syndrome patients to develop approaches for earlier diagnosis and interventions. Spero, who visits the Clinical Center annually and communicates with the NIH team on a weekly basis, has been so inspired by the experience that she even chose to feature Dr. Freeman in one of her recent podcasts.
Unlike Spero, I don’t have a podcast—at least not yet. But I do have a blog, and Spero was kind enough to respond to a few of my questions on rare diseases and medical research. So, I’m sharing her thoughts below—I hope you are inspired by them as much as I was!
Why do you feel it is important for people with rare diseases to take part in medical research?
Without research, we can’t make any improvements, changes or find cures. Participating in medical research allows researchers and doctors to learn about the trends (or lack of) between patients, and determine what’s working and what’s not.
What have your own experiences been with the health-care system and medical research?
When I was younger, I really didn’t want to be a specimen. I was going through so much trying to find answers and treatments for myself that it was hard to think about how it would help other patients down the road to be sharing my experiences. I didn’t want to add another doctor’s visit to my schedule. After coming to NIH in 2012, I recognized the importance of being part of the research because it could essentially help me, other patients and for early detection of rare diseases. I recognize that the medical researchers are often much more compassionate than many doctors who simply treat symptoms. Researchers are curious and genuinely care to understand you and your story.
Your podcast is fantastic. How has it affected you to hear and share the stories of so many people affected by rare diseases?
I was definitely aware how many people were living with rare diseases, but I was surprised by how many people were willing to share their stories on my show and how many people wanted to listen to these stories. I hadn’t heard stories being shared in this way around this topic and I wanted to be the one who brought them to life. Many of my guests haven’t publicly (let alone with friends or family) shared their stories so I’m honored that they’re willing to do it with me. They see how important it is to have these conversations and to educate people on what it’s like to have an invisible illness.
What would you tell someone who’s just learned he or she has a rare disease?
You don’t have to do this alone! Find a team of medical professionals you trust to support you. I spent most of my life without a team of doctors that I loved and truly understood me, and now I can’t imagine my life without my team at NIH. Also, talk to your loved ones—let them know what you’re feeling and discuss how they can support you. This is likely new for them too and there’s no right way of navigating and managing a rare disease.
What would you tell a young person who’s considering becoming a rare disease researcher?
Thank you for your interest in doing this! We need more compassionate, curious and passionate people doing this work and investing their time to learn more and help find answers for rare diseases. Please treat us with respect and care.
If you could change one thing in the medical care/research of rare disease, what would it be? And what about in society in general?
There’s a way to do your job without treating patients like guinea pigs. We’re humans too, and we’re humans who have likely been through the wringer in the medical world. Be kind to us. Treat us the way you’d like to be treated. Compassion seems to be a word I’m using a lot. I think society can be more compassionate towards one another especially around rare disease. You can never fully understand what someone is going through so ask questions, show you care and treat people with kindness.
What are your hopes for the future?
I’d love there to be more answers and solutions for navigating a rare disease. A lot of the treatments I do are based on trial-and-error. What works for one patient definitely doesn’t always work for me. So, we’re constantly trying to navigate what works best for me. I’d love to see a cure to be found for Hyper IgE/Job’s Syndrome, as well as other rare diseases.
Podcast Series: Made Visible
NIH Patient Shares Stories of ‘Invisible Illness,’ The NIH Record, February 8, 2019
Hyper-Immunoglobulin E Syndrome (HIES) (National Institute of Allergy and Infectious Diseases/NIH)
Rare Disease Day at NIH 2019 (National Center for Advancing Translational Sciences/NIH)
Video: Rare Disease Patient Profiles (NCATS)
Undiagnosed Diseases Network (Common Fund/NIH)
Video: One in a Million (Undiagnosed Diseases Network, University of Utah Health, Salt Lake City)
Posted on by Dr. Francis Collins
Credit: Michele Ardolino, University of Ottawa, and Brian Weist, Gilead Sciences, Foster City, CA
Cancer immunotherapies, which enlist a patient’s own immune system to attack and shrink developing tumors, have come a long way in recent years, leading in some instances to dramatic cures of widely disseminated cancers. But, as this video highlights, new insights from immunology are still being revealed that may provide even greater therapeutic potential.
Our immune system comes equipped with all kinds of specialized cells, including the infection-controlling Natural Killer (NK) cells. The video shows an army of NK cells (green) attacking a tumor in a mouse (blood vessels, blue) treated with a well-established type of cancer immunotherapy known as a checkpoint inhibitor. What makes the video so interesting is that researchers didn’t think checkpoint inhibitors could activate NK cells.