Dr. Francis Collins
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
Drug overdoses continue to take far too many lives, driven primarily by the opioid crisis (though other drugs, such as methamphetamine and cocaine, are also major concerns). While NIH’s Helping to End Addiction Long-term (HEAL) Initiative is taking steps to address this terrible crisis, new findings serve as another wake-up call that young people battling opioid addiction need a lot more assistance to get back on the right track.
In a study of more than 3,600 individuals, aged 13-22, who survived an opioid overdose, an NIH-funded team found that only about one-third received any kind of follow-up addiction treatment . Even more troubling, less than 2 percent of these young people received the gold standard approach of medication treatment.
The findings reported in JAMA Pediatrics come from Rachel Alinsky, an adolescent medicine and addiction medicine fellow at Johns Hopkins Children’s Center, Baltimore. She saw first-hand the devastating toll that opioids are taking on our youth.
Alinsky also knew that nationally more than 4,000 fatal opioid overdoses occurred in people between the ages of 15 and 24 in 2016 . Likewise, rates of nonfatal opioid overdoses for teens and young adults also have been escalating, leading to more than 7,000 hospitalizations and about 28,000 emergency department visits in 2015 alone .
In the latest study, Alinsky wanted to find out whether young people who overdose receive timely treatment to help prevent another life-threatening emergency. According to our best evidence-based guidelines, timely treatment for youth with an opioid addiction should include medication, ideally along with behavioral interventions.
That’s because opioid addiction rewires the brain—will power alone is simply not sufficient to achieve and sustain recovery. After one overdose, the risk of dying from another one rises dramatically. So, it is critical to get those who survived an overdose into effective treatment right away.
Alinsky and her team dove into the best-available dataset, consisting of data on more than 4 million mostly low-income adolescents and young adults who’d been enrolled in Medicaid for at least six months in 16 states. The sample included 3,606 individuals who’d been seen by a doctor and diagnosed with opioid poisoning. A little over half of them were female; most were non-Hispanic whites.
Heroin accounted for about a quarter of those overdoses. The rest involved other opioids, most often prescription painkillers. However, the researchers note that some overdoses attributed to heroin might have been caused by the powerful synthetic opioid fentanyl. The use of fentanyl, often mixed with heroin, was on the rise in the study’s final years, but it was rarely included in drug tests at the time.
Less than 20 percent of young people in the sample received a diagnosis of opioid use disorder, or a problematic pattern of opioid use resulting in impairment or distress. What’s more, in the month following an overdose, few received the current standard for addiction treatment, which should include behavioral therapy and treatment with one of three drugs: buprenorphine, naltrexone, or methadone.
Drilling a little deeper into the study’s findings:
• 68.9 percent did not receive addiction treatment of any kind.
• 29.3 percent received behavioral health services alone.
• Only 1.9 percent received one of three approved medications for opioid use disorder.
It’s been estimated previously that teens and young adults are one-tenth as likely as adults 25 years and older to get the recommended treatment for opioid use disorder . How can that be? The researchers suggest that one factor might be inexperience among pediatricians in diagnosing and treating opioid addiction. They also note that, even when the problem is recognized, doctors sometimes struggle to take the next step and connect young people with addiction treatment facilities that are equipped to provide the needed treatment to adolescents.
As this new study shows, interventions designed to link teens and young adults with the needed recovery treatment and care are desperately needed. As we continue to move forward in tackling this terrible crisis through the NIH’s HEAL Initiative and other efforts, finding ways to overcome such systemic barriers and best engage our youth in treatment, including medication, will be essential.
 Receipt of addiction treatment after opioid overdose among Medicaid-enrolled adolescents and young adults. Alinsky RH, Zima BT, Rodean J, Matson PA, Larochelle MR, Adger H Jr, Bagley SM, Hadland SE. JAMA Pediatr. 2020 Jan 6:e195183.
 Overdose death rates. National Institute on Drug Abuse, NIH.
 2018 annual surveillance drug-related risks and outcomes—United States: surveillance special report. Centers for Disease Control and Prevention.
 Medication-assisted treatment for adolescents in specialty treatment for opioid use disorder. Feder KA, Krawczyk N, Saloner B. J Adolesc Health. 2017 Jun;60(6):747-750.
Opioid Overdose Crisis (National Institute on Drug Abuse/NIH)
Opioid Overdose (Centers for Disease Control and Prevention, Atlanta)
Decisions in Recovery: Treatment for Opioid Use Disorder (Substance Abuse and Mental Health Services Administration, Rockville, MD)
Rachel Alinsky (Johns Hopkins University Children’s Center, Baltimore)
NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse
Posted on by Dr. Francis Collins
You might think nutrient-sensing cells in the human gastrointestinal (GI) tract would have no connection whatsoever to autism spectrum disorder (ASD). But if Diego Bohórquez’s “big idea” is correct, these GI cells, called neuropods, could one day help to provide a direct link into understanding and treating some aspects of autism and other brain disorders.
Bohórquez, a researcher at Duke University, Durham, NC, recently discovered that cells in the intestine, previously known for their hormone-releasing ability, form extensions similar to neurons. He also found that those extensions connect to nerve fibers in the gut, which relay signals to the vagus nerve and onward to the brain. In fact, he found that those signals reach the brain in milliseconds .
Bohórquez has dedicated his lab to studying this direct, high-speed hookup between gut and brain and its impact on nutrient sensing, eating, and other essential behaviors. Now, with support from a 2019 NIH Director’s New Innovator Award, he will also explore the potential for treating autism and other brain disorders with drugs that act on the gut.
Bohórquez became interested in autism and its possible link to the gut-brain connection after a chance encounter with Geraldine Dawson, director of the Duke Center for Autism and Brain Development. Dawson mentioned that autism typically affects multiple organ systems.
With further reading, he discovered that kids with autism frequently cope with GI issues, including bowel inflammation, abdominal pain, constipation, and/or diarrhea . They often also show unusual food-related behaviors, such as being extremely picky eaters. But his curiosity was especially piqued by evidence that certain gut microbes can influence abnormal behaviors in mice that model autism.
With his New Innovator Award, Bohórquez will study neuropods and the gut-brain connection in a mouse model of autism. Using the tools of optogenetics, which make it possible to activate cells with light, he’ll also see whether autism-like symptoms in mice can be altered or alleviated by controlling neuropods in the gut. Those symptoms include anxiety, repetitive behaviors, and lack of interest in interacting with other mice. He’ll also explore changes in the animals’ eating habits.
In another line of study, he will take advantage of intestinal tissue samples collected from people with autism. He’ll use those tissues to grow and then examine miniature intestinal “organoids,” looking for possible evidence that those from people with autism are different from others.
For the millions of people now living with autism, no truly effective drug therapies are available to help to manage the condition and its many behavioral and bodily symptoms. Bohórquez hopes one day to change that with drugs that act safely on the gut. In the meantime, he and his fellow “GASTRONAUTS” look forward to making some important and fascinating discoveries in the relatively uncharted territory where the gut meets the brain.
 A gut-brain neural circuit for nutrient sensory transduction. Kaelberer MM, Buchanan KL, Klein ME, Barth BB, Montoya MM, Shen X, Bohórquez DV. Science. 2018 Sep 21;361(6408).
 Association of maternal report of infant and toddler gastrointestinal symptoms with autism: evidence from a prospective birth cohort. Bresnahan M, Hornig M, Schultz AF, Gunnes N, Hirtz D, Lie KK, Magnus P, Reichborn-Kjennerud T, Roth C, Schjølberg S, Stoltenberg C, Surén P, Susser E, Lipkin WI. JAMA Psychiatry. 2015 May;72(5):466-474.
Autism Spectrum Disorder (National Institute of Mental Health/NIH)
Bohórquez Lab (Duke University, Durham, NC)
Bohórquez Project Information (NIH RePORTER)
NIH Director’s New Innovator Award (Common Fund)
NIH Support: Common Fund; National Institute of Mental Health
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