cancer immunotherapy
How to Feed a Macrophage
Posted on by Lawrence Tabak, D.D.S., Ph.D.
For Annalise Bond, a graduate student in the lab of Meghan Morrissey, University of California, Santa Barbara (UCSB), macrophages are “the professional eaters of our immune system.” Every minute of every day, macrophages somewhere in the body are gorging themselves to remove the cellular debris that builds up in our tissues and organs.
In this image, Bond caught several macrophages (green) doing what they do best: shoveling it in—in this case, during a lab experiment. The macrophages are consuming silica beads (purple) prepared with biochemicals that whet their appetites. Each bead measures about five microns in diameter. That’s roughly the size of a bacterium or a spent red blood cell—debris that a macrophage routinely consumes.
When Bond snapped this image, she noticed a pattern that reminded her of a childhood tabletop game called Hungry Hungry Hippos. Kids press a lever attached to the mouth of a plastic hippo, its lower jaw flaps open, and the challenge is to fill the mouth with as many marbles as possible . . . just like the macrophages eating beads.
Bond adjusted the colors in the photo to make them pop. She then entered it into UCSB’s 2023 Art of Science contest with the caption of Hungry Hungry Macrophages, winning high marks for drawing the association.
Though the caption was written in fun, Bond studies in earnest a fascinating biological question: How do macrophages know what to eat in the body and what to leave untouched?
In her studies, Bond coats the silica beads shown above with a lipid bilayer to mimic a cell membrane. To that coating, she adds various small molecules and proteins as “eat-me” signals often found on the surface of dying cells. Some of the signals are well characterized; but many aren’t, meaning there’s still a lot to learn about what makes a macrophage “particularly hungry” and what makes a particular target cell “extra tasty.”
Capturing fluorescent images of macrophages under the microscope, Bond counts up how many beads are eaten. Beads bearing no signal to stimulate their appetite might get eaten occasionally. But when an especially enticing signal is added, macrophages will gorge themselves until they can’t eat anymore.
In the experiment pictured above, the beads contain the antibody immunoglobulin G (IgG), which tags foreign pathogens for macrophage removal. Interestingly, IgG antibody responses also play an important role in cancer immunotherapies, in which the immune system is unleashed to fight cancer.
Among its many areas of study, the NIH-supported Morrissey lab’s wants to understand better how macrophages interact with cancer cells. They want to learn how to make cancer cells even tastier to macrophages and program their elimination from the body. Sorting out the signals will be challenging, but we know that macrophages will take a bite at the right ones. They are, after all, professional eaters.
Links:
Cancer Immunotherapy (NIH)
Annalise Bond (University of California, Santa Barbara)
Morrissey Lab (University of California, Santa Barbara)
Art of Science (University of California, Santa Barbara)
NIH Support: National Institute of General Medical Sciences
New Tool Predicts Response to Immunotherapy in Lung Cancer Patients
Posted on by Douglas M. Sheeley, Sc.D., NIH Common Fund
With just a blood sample from a patient, a promising technology has the potential to accurately diagnose non-small cell lung cancer (NSCLC), the most-common form of the disease, more than 90 percent of the time. The same technology can even predict from the same blood sample whether a patient will respond well to a targeted immunotherapy treatment.
This work is a good example of research supported by the NIH Common Fund. Many Common Fund programs support development of new tools that catalyze research across the full spectrum of biomedical science without focusing on a single disease or organ system.
The emerging NSCLC prediction technology was developed as part of our Extracellular RNA Communication Program. The program develops technologies to understand RNA circulating in the body, known as extracellular RNA (exRNA). These molecules can be easily accessed in bodily fluids such as blood, urine, and saliva, and they have enormous potential as biomarkers to better understand cancer and other diseases.
When the body’s immune system detects a developing tumor, it activates various immune cells that work together to kill the suspicious cells. But many tumors have found a way to evade the immune system by producing a protein called PD-L1.
Displayed on the surface of a cancer cell, PD-L1 can bind to a protein found on immune cells with the similar designation of PD-1. The binding of the two proteins keeps immune cells from killing tumor cells. One type of immunotherapy interferes with this binding process and can restore the natural ability of the immune system to kill the tumor cells.
However, tumors differ from person to person, and this form of cancer immunotherapy doesn’t work for everyone. People with higher levels of PD-L1 in their tumors generally have better response rates to immunotherapy, and that’s why oncologists test for the protein before attempting the treatment.
Because cancer cells within a tumor can vary greatly, a single biopsy taken at a single site in the tumor may miss cells with PD-L1. In fact, current prediction technologies using tissue biopsies correctly predict just 20 – 40 percent of NSCLC patients who will respond well to immunotherapy. This means some people receive immunotherapy who shouldn’t, while others don’t get it who might benefit.
To improve these predictions, a research team led by Eduardo Reátegui, The Ohio State University, Columbus, engineered a new technology to measure exRNA and proteins found within and on the surface of extracellular vesicles (EVs) [1]. EVs are tiny molecular containers released by cells. They carry RNA and proteins (including PD-L1) throughout the body and are known to play a role in communication between cells.
As the illustration above shows, EVs can be shed from tumors and then circulate in the bloodstream. That means their characteristics and internal cargo, including exRNA, can provide insight into the features of a tumor. But collecting EVs, breaking them open, and pooling their contents for assessment means that molecules occurring in small quantities (like PD-L1) can get lost in the mix. It also exposes delicate exRNA molecules to potential breakdown outside the protective EV.
The new technology solves these problems. It sorts and isolates individual EVs and measures both PD-1 and PD-L1 proteins, as well as exRNA that contains their genetic codes. This provides a more comprehensive picture of PD-L1 production within the tumor compared to a single biopsy sample. But also, measuring surface proteins and the contents of individual EVs makes this technique exquisitely sensitive.
By measuring proteins and the exRNA cargo from individual EVs, Reátegui and team found that the technology correctly predicted whether a patient had NSCLC 93.2 percent of the time. It also predicted immunotherapy response with an accuracy of 72.2 percent, far exceeding the current gold standard method.
The researchers are working on scaling up the technology, which would increase precision and allow for more simultaneous measurements. They are also working with the James Comprehensive Cancer Center at The Ohio State University to expand their testing. That includes validating the technology using banked clinical samples of blood and other bodily fluids from large groups of cancer patients. With continued development, this new technology could improve NSCLC treatment while, critically, lowering its cost.
The real power of the technology, though, lies in its flexibility. Its components can be swapped out to recognize any number of marker molecules for other diseases and conditions. That includes other cancers, neurodegenerative diseases, traumatic brain injury, viral diseases, and cardiovascular diseases. This broad applicability is an example of how Common Fund investments catalyze advances across the research spectrum that will help many people now and in the future.
Reference:
[1] An immunogold single extracellular vesicular RNA and protein (AuSERP) biochip to predict responses to immunotherapy in non-small cell lung cancer patients. Nguyen LTH, Zhang J, Rima XY, Wang X, Kwak KJ, Okimoto T, Amann J, Yoon MJ, Shukuya T, Chiang CL, Walters N, Ma Y, Belcher D, Li H, Palmer AF, Carbone DP, Lee LJ, Reátegui E. J Extracell Vesicles. 11(9):e12258. doi: 10.1002/jev2.12258.
Links:
Video: Unlocking the Mysteries of Extracellular RNA Communication (Common Fund)
Extracellular RNA Communication Program (ERCC) (Common Fund)
Upcoming Meeting: ERCC19 Research Meeting (May 1-2, 2023)
Eduardo Reátegui Group for Bioengineering Research (The Ohio State University College of Engineering, Columbus)
Note: Dr. Lawrence Tabak, who performs the duties of the NIH Director, has asked the heads of NIH’s Institutes, Centers, and Offices to contribute occasional guest posts to the blog to highlight some of the interesting science that they support and conduct. This is the 27th in the series of NIH guest posts that will run until a new permanent NIH director is in place.
Celebrating NIH Science, Blogs, and Blog Readers!
Posted on by Dr. Francis Collins
Happy holidays to one and all! As you may have heard, this is my last holiday season as the Director of the National Institutes of Health (NIH)—a post that I’ve held for the past 12 years and four months under three U.S. Presidents. And, wow, it really does seem like only yesterday that I started this blog!
At the blog’s outset, I said my goal was to “highlight new discoveries in biology and medicine that I think are game changers, noteworthy, or just plain cool.” More than 1,100 posts, 10 million unique visitors, and 13.7 million views later, I hope you’ll agree that goal has been achieved. I’ve also found blogging to be a whole lot of fun, as well as a great way to expand my own horizons and share a little of what I’ve learned about biomedical advances with people all across the nation and around the world.
So, as I sign off as NIH Director and return to my lab at NIH’s National Human Genome Research Institute (NHGRI), I want to thank everyone who’s ever visited this Blog—from high school students to people with health concerns, from biomedical researchers to policymakers. I hope that the evidence-based information that I’ve provided has helped and informed my readers in some small way.
In this my final post, I’m sharing a short video (see above) that highlights just a few of the blog’s many spectacular images, many of them produced by NIH-funded scientists during the course of their research. In the video, you’ll see a somewhat quirky collection of entries, but hopefully you will sense my enthusiasm for the potential of biomedical research to fight human disease and improve human health—from innovative immunotherapies for treating cancer to the gift of mRNA vaccines to combat a pandemic.
Over the years, I’ve blogged about many of the bold, new frontiers of biomedicine that are now being explored by research teams supported by NIH. Who would have imagined that, within the span of a dozen years, precision medicine would go from being an interesting idea to a driving force behind the largest-ever NIH cohort seeking to individualize the prevention and treatment of common disease? Or that today we’d be deep into investigations of precisely how the human brain works, as well as how human health may benefit from some of the trillions of microbes that call our bodies home?
My posts also delved into some of the amazing technological advances that are enabling breakthroughs across a wide range of scientific fields. These innovative technologies include powerful new ways of mapping the atomic structures of proteins, editing genetic material, and designing improved gene therapies.
So, what’s next for NIH? Let me assure you that NIH is in very steady hands as it heads into a bright horizon brimming with exceptional opportunities for biomedical research. Like you, I look forward to discoveries that will lead us even closer to the life-saving answers that we all want and need.
While we wait for the President to identify a new NIH director, Lawrence Tabak, who has been NIH’s Principal Deputy Director and my right arm for the last decade, will serve as Acting NIH Director. So, keep an eye out for his first post in early January!
As for me, I’ll probably take a little time to catch up on some much-needed sleep, do some reading and writing, and hopefully get out for a few more rides on my Harley with my wife Diane. But there’s plenty of work to do in my lab, where the focus is on type 2 diabetes and a rare disease of premature aging called Hutchinson-Gilford Progeria Syndrome. I’m excited to pursue those research opportunities and see where they lead.
In closing, I’d like to extend my sincere thanks to each of you for your interest in hearing from the NIH Director—and supporting NIH research—over the past 12 years. It’s been an incredible honor to serve you at the helm of this great agency that’s often called the National Institutes of Hope. And now, for one last time, Diane and I take great pleasure in sending you and your loved ones our most heartfelt wishes for Happy Holidays and a Healthy New Year!
Teaching the Immune System to Attack Cancer with Greater Precision
Posted on by Dr. Francis Collins
To protect humans from COVID-19, the Pfizer and Moderna mRNA vaccines program human cells to translate the injected synthetic messenger RNA into the coronavirus spike protein, which then primes the immune system to arm itself against future appearances of that protein. It turns out that the immune system can also be trained to spot and attack distinctive proteins on cancer cells, killing them and leaving healthy cells potentially untouched.
While these precision cancer vaccines remain experimental, researchers continue to make basic discoveries that move the field forward. That includes a recent NIH-funded study in mice that helps to refine the selection of protein targets on tumors as a way to boost the immune response [1]. To enable this boost, the researchers first had to discover a possible solution to a longstanding challenge in developing precision cancer vaccines: T cell exhaustion.
The term refers to the immune system’s complement of T cells and their capacity to learn to recognize foreign proteins, also known as neoantigens, and attack them on cancer cells to shrink tumors. But these responding T cells can exhaust themselves attacking tumors, limiting the immune response and making its benefits short-lived.
In this latest study, published in the journal Cell, Tyler Jacks and Megan Burger, Massachusetts Institute of Technology, Cambridge, help to explain this phenomenon of T cell exhaustion. The researchers found in mice with lung tumors that the immune system initially responds as it should. It produces lots of T cells that target many different cancer-specific proteins.
Yet there’s a problem: various subsets of T cells get in each other’s way. They compete until, eventually, one of those subsets becomes the dominant T cell type. Even when those dominant T cells grow exhausted, they still remain in the tumor and keep out other T cells, which might otherwise attack different neoantigens in the cancer.
Building on this basic discovery, the researchers came up with a strategy for developing cancer vaccines that can “awaken” T cells and reinvigorate the body’s natural cancer-fighting abilities. The strategy might seem counterintuitive. The researchers vaccinated mice with neoantigens that provide a weak but encouraging signal to the immune cells responsible for presenting the distinctive cancer protein target, or antigen, to T cells. It’s those T cells that tend to get suppressed in competition with other T cells.
When the researchers vaccinated the mice with one of those neoantigens, the otherwise suppressed T cells grew in numbers and better targeted the tumor. What’s more, the tumors shrank by more than 25 percent on average.
Research on this new strategy remains in its early stages. The researchers hope to learn if this approach to cancer vaccines might work even better when used in combination with immunotherapy drugs, which unleash the immune system against cancer in other ways.
It’s also possible that the recent and revolutionary success of mRNA vaccines for preventing COVID-19 actually could help. An important advantage of mRNA is that it’s easy for researchers to synthesize once they know the specific nucleic acid sequence of a protein target, and they can even combine different mRNA sequences to make a multiplex vaccine that primes the immune system to recognize multiple neoantigens. Now that we’ve seen how well mRNA vaccines work to prompt a desired immune response against COVID-19, this same technology can be used to speed the development and testing of future vaccines, including those designed precisely to fight cancer.
Reference:
[1] Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors. Burger ML, Cruz AM, Crossland GE, Gaglia G, Ritch CC, Blatt SE, Bhutkar A, Canner D, Kienka T, Tavana SZ, Barandiaran AL, Garmilla A, Schenkel JM, Hillman M, de Los Rios Kobara I, Li A, Jaeger AM, Hwang WL, Westcott PMK, Manos MP, Holovatska MM, Hodi FS, Regev A, Santagata S, Jacks T. Cell. 2021 Sep 16;184(19):4996-5014.e26.
Links:
Cancer Treatment Vaccines (National Cancer Institute/NIH)
The Jacks Lab (Massachusetts Institute of Technology, Cambridge)
NIH Support: National Cancer Institute; National Heart, Lung, and Blood Institute
An Evolutionary Guide to New Immunotherapies
Posted on by Dr. Francis Collins
One of the best ways to learn how something works is to understand how it’s built. How it came to be. That’s true not only if you play a guitar or repair motorcycle engines, but also if you study the biological systems that make life possible. Evolutionary studies, comparing the development of these systems across animals and organisms, are now leading to many unexpected biological discoveries and promising possibilities for preventing and treating human disease.
While there are many evolutionary questions to ask, Brenda Bass, a distinguished biochemist at University of Utah, Salt Lake City, has set her sights on a particularly profound one: How has innate immunity evolved through the millennia in all living things, including humans? Innate immunity is the immune system’s frontline defense, the first responders that take control of an emerging infectious situation and, if needed, signal for backup.
Exploring the millennia for clues about innate immunity takes a special team, and Bass has assembled a talented one. It includes her Utah colleague Nels Elde, a geneticist; immunologist Dan Stetson, University of Washington, Seattle; and biochemist Jane Jackman, Ohio State University, Columbus.
With a 2020 NIH Director’s Transformative Research Award, this hard-working team will embark on studies looking back at 450 million years of evolution: the point in time when animals diverged to develop very distinct methods of innate immune defense [1]. The team members hope to uncover new possibilities encoded in the innate immune system, especially those that might be latent but still workable. The researchers will then explore whether their finds can be repurposed not only to boost our body’s natural response to external threats but also to internal threats like cancer.
Bass brings a unique perspective to the project. As a postdoc in the 1980s, she stumbled upon a whole new class of enzymes, called ADARs, that edit RNA [2]. Their function was mysterious at the time. It turns out that ADARs specifically edit a molecule called double-stranded RNA (dsRNA). When viruses infect cells in animals, including humans, they make dsRNA, which the innate immune system detects as a sign that a cell has been invaded.
It also turns out that animal cells make their own dsRNA. Over the years, Bass and her lab have identified thousands of dsRNAs made in animal cells—in fact, a significant number of human genes produce dsRNA [3]. Also interesting, ADARs are crucial to marking our own dsRNA as “self” to avoid triggering an immune response when we don’t need it [4].
Bass and others have found that evolution has produced dramatic differences in the biochemical pathways powering the innate immune system. In vertebrate animals, dsRNA leads to release of the immune chemical interferon, a signaling pathway that invertebrate species don’t have. Instead, in response to detecting dsRNA from an invader, and repelling it, worms and other invertebrates trigger a gene-silencing pathway known as RNA interference, or RNAi.
With the new funding, Bass and team plan to mix and match immune strategies from simple and advanced species, across evolutionary time, to craft an entirely new set of immune tools to fight disease. The team will also build new types of targeted immunotherapies based on the principles of innate immunity. Current immunotherapies, which harness a person’s own immune system to fight disease, target infections, autoimmune disorders, and cancer. But they work through our second-line adaptive immune response, which is a biological system unique to vertebrates.
Bass and her team will first hunt for more molecules like ADARs: innate immune checkpoints, as they refer to them. The name comes from a functional resemblance to the better-known adaptive immune checkpoints PD-1 and CTLA-4, which sparked a revolution in cancer immunotherapy. The team will run several screens that sort molecules successful at activating innate immune responses—both in invertebrates and in mammals—hoping to identify a range of durable new immune switches that evolution skipped over but that might be repurposed today.
Another intriguing direction for this research stems from the observation that decreasing normal levels of ADARs in tumors kickstarts innate immune responses that kill cancer cells [5]. Along these lines, the scientists plan to test newly identified immune switches to look for novel ways to fight cancer where existing approaches have not worked.
Evolution is the founding principle for all of biology—organisms learn from what works to improve their ability to survive. In this case, research to re-examine such lessons and apply them for new uses may help transform bygone evolution into a therapeutic revolution!
References:
[1] Evolution of adaptive immunity from transposable elements combined with innate immune systems. Koonin EV, Krupovic M. Nat Rev Genet. 2015 Mar;16(3):184-192.
[2] A developmentally regulated activity that unwinds RNA duplexes. Bass BL, Weintraub H. Cell. 1987 Feb 27;48(4):607-613.
[3] Mapping the dsRNA World. Reich DP, Bass BL. Cold Spring Harb Perspect Biol. 2019 Mar 1;11(3):a035352.
[4] To protect and modify double-stranded RNA – the critical roles of ADARs in development, immunity and oncogenesis. Erdmann EA, Mahapatra A, Mukherjee P, Yang B, Hundley HA. Crit Rev Biochem Mol Biol. 2021 Feb;56(1):54-87.
[5] Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, et al. Nature. 2019 Jan;565(7737):43-48.
Links:
Bass Lab (University of Utah, Salt Lake City)
Elde Lab (University of Utah)
Jackman Lab (Ohio State University, Columbus)
Stetson Lab (University of Washington, Seattle)
Bass/Elde/Jackman/Stetson Project Information (NIH RePORTER)
NIH Director’s Transformative Research Award Program (Common Fund)
NIH Support: Common Fund; National Cancer Institute
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