Research Area: Cancer Biology
Collaborators investigate colon health with novel tools
Deborah Halber | Spectrum
November 9, 2021
In a building at the edge of the Massachusetts General Hospital (MGH) complex, Ömer Yilmaz, MD, and a group of pathology residents gather around a microscope. A resident reads from a chart: a growth was found in the intestine of a patient who had complained of abdominal pain.
Yilmaz, an MIT cancer researcher and a gastrointestinal pathologist, hoped a closer look at the tumor would reveal a noncancerous collection of fat cells or lymphoid cells.
It had taken a couple of days to prepare the biopsy. Somewhere in the hospital, the patient and her family were anxiously awaiting a diagnosis. Yilmaz leaned forward and adjusted the focus on the microscope.
On the tracks of cancer
If the long, twisting tube of the human digestive tract were stretched out straight, it would extend 30 feet, and its absorptive surface area is roughly comparable to the size of a tennis court. A significant chunk of that tube is the large intestine, an intricate place rife with microscopic structures called niches and crypts, evoking an underground cavern or the ocean floor. Besides the skin, the intestines are the body’s primary barrier against external invaders.
Yilmaz, an associate professor of biology at the Koch Institute for Integrative Cancer Research, believes certain cancers and diseases such as inflammatory bowel disease originate with a breakdown of the intestine’s protective barrier. Diet appears to affect intestinal stem cells; these cells can morph into a variety of cell types, and changes in stem cells can lead to cancer, but no one understands exactly how this occurs.
That’s where Yilmaz’s partnership with MIT biomedical engineer and chemist Alex Shalek comes in. Yilmaz and Shalek are both members of the MIT Stem Cell Initiative, which focuses on fundamental biological questions about benign and cancerous adult stem cells.
Shalek, a core member of the Institute for Medical Engineering and Science (IMES), a member of the Koch Institute, and an associate professor of chemistry, develops experimental and computational tools that provide researchers with detailed snapshots of what’s going on inside living cells at a moment in time. Some of these tools, Yilmaz hoped, would enable him to see how intestinal cells react when they encounter an influx of fat or are deprived of food for hours or days.
“In the past, people would have taken a piece of gut that had many different cell types and said, ‘What changes, on average, under different dietary conditions?’” Shalek says. His tools give him and Yilmaz more precise information, providing a window into the discrete molecular responses of individual cells within the colon.
The role of stem cells
Growing up in Battle Creek, Michigan, Yilmaz spent all his free time trailing after his father, a physician who had immigrated from Turkey. He’d make hospital rounds with his dad, visiting the pathology and radiology labs. As Yilmaz grew older, the two would talk about the mechanisms underlying disease.
After completing his MD/PhD at the University of Michigan, Yilmaz did his residency in pathology, the study of disease, at MGH. He began working at the Whitehead Institute with MIT biology professor David M. Sabatini, a pioneer in elucidating the mechanisms under-lying the regulation of growth and metabolism in mammals. Yilmaz had long been fascinated with stem cells’ seemingly miraculous ability to become any kind of cell the body needed. In adults, stem cells are relatively rare, best studied in bone marrow.
When scientists first found stem cells in the intestine in 2007, Yilmaz shifted his research focus. “As soon as intestinal stem cells were identified, I became interested in understanding how they are regulated by diet and aging,” he says.
“We know obesity elevates cancer risk in a wide range of tissues, including the colon, but we don’t know exactly how. And fasting regimens have been known to improve organ and tissue health, but this, too, is not well understood.”
To better study the transition from healthy to diseased cells in the colon, Yilmaz’s team generated colon tumors in mice that closely resemble human tumors. These colon tumors from mice or humans can be grown in culture, creating miniature three-dimensional tumors called organoids.
Subjecting the organoids to different conditions, Yilmaz and Sabatini found that in mice, age-related loss of stem cell function can be reversed by a 24-hour fast. Other studies looked at the type of high-fat diet leading to obesity. Yilmaz determined that a high-fat diet boosted the population of intestinal stem cells and generated even more cells that behaved like stem cells. These stem cells and stem-like cells are more likely to give rise to intestinal tumors.
What’s happening inside
In the microenvironment of the digestive system, the single layer of epithelial cells that line the colon die after only a few days of ferrying nutrients into the bloodstream and lymphatic system.
Stem cells sheltered in protected spaces with fanciful names like the crypts of Lieberkühn generate a hundred grams of new intestinal tissue every day. The source of all the epithelial cells as well as the cells of the villi, a velvety layer of fingerlike projections that line the intestine, stem cells repair and replace tissue continually assaulted by stomach acid, pancreatic enzymes, bile, fats, and bacteria.
Nearby cells guard the stem cells by secreting agents that fight off harmful bacteria, fungi, and viruses and help regulate the composition of the microbiome.
Most of the body’s stem cells, like those deep within bone marrow, are not nearly as prolific as intestinal stem cells, likely because there’s a risk associated with the stem cells’ ability to rapidly replace themselves: mutations.
At the heart of a cell’s behavior is its messenger RNA, or mRNA, the technology used in the Moderna and Pfizer Covid-19 vaccines. These mRNA vaccines teach cells how to make a protein that triggers an immune response to the virus. Each mRNA transcript, a single strand of RNA carrying a specific genetic instruction from the DNA in the nucleus to the cell’s protein-making machinery, determines which protein gets made to help support the cell’s activity.
“From a snapshot of all of the cell’s mRNA, its transcriptome, we can see how it is trying to respond to change,” Shalek says.
Shalek’s tools help him and Yilmaz measure the properties of multiple types of intestinal cells—immune cells, stem cells, and epithelial cells, to name a few—at once to see precisely how these otherwise invisible, minute features collectively orchestrate tissue-wide responses to external signals.
Sequencing a cell’s mRNA makeup requires smashing the cell open and collecting all of its transcripts. Shalek jokingly likened the process to an alien invader beaming human specimens up to a spaceship and investigating what’s happening inside them.
One of the methods Shalek helped develop tags each mRNA within a cell so that it can be traced back to its cell of origin even after it’s been ripped apart. The inexpensive, portable system, called Seq-Well, looks like an ice cube tray. Around the size of a stick of gum, it contains roughly a hundred thousand miniature wells, each approximately 50-by-50-by-50 microns.
Each cell is deposited into its own well, which contains a bead coated with uniquely barcoded DNA molecules; those DNA molecules are designed to latch onto mRNA and ignore the rest of the cell’s components. The wells are sealed and the cells broken apart. The beads are then extracted, processed, and analyzed, providing a record of each cell’s intentions in its last living moments.
The fact that the system can look simultaneously at thousands of individual cells of any type allows Shalek and Yilmaz to check the effect of nutrients on epithelial cells, immune cells, and stem cells all at once.
The Shalek lab is also developing screening tools that are particularly useful for exposing the Yilmaz lab’s organoids to hundreds of nutrients or drugs at one time, potentially reducing the effort needed to identify substances that boost or hinder stem cell function.
Already, Yilmaz and Shalek have used Seq-Well to identify an enzyme that could be a potential future target for a drug that would counter the negative effects of a high-fat diet on intestinal stem cells. More broadly, Yilmaz says, their collaboration is helping develop a very nuanced understanding of a very complex organ.
“Understanding that complexity is what has really driven our collaboration,” Yilmaz says. “Alex has developed the tools that enable us to dissect out individual cell populations and start to understand how environmental factors impact gene expression.”
“Scientists have spent the past 40 years delineating the genetic drivers of colon cancer, and we still have more to learn. But we’ve now entered the era in which we want to understand the impact of environmental and host factors,” Yilmaz says.
Yilmaz hopes to identify nutrients and metabolites that can enhance stem cell function to repair damage after injury, or to identify mechanisms that dampen tumor formation. In addition, biomarkers such as levels of certain substances in the blood could be a key to early intervention, he says.
“Can we identify which obese patients are more prone to developing colon cancer? If so, can we identify therapies that go after weaknesses in their tumors?”
Battling colon cancer
During the time Yilmaz spends at MGH, he looks at slide after slide of biopsied cells. Normal epithelial cells line up in a single, orderly row. After 15 years in medicine, the twisted appearance of diseased cells still shocks him. “You know, in most cases, the number one predictor of how bad a tumor is going to behave isn’t its genetic signature,” he says. “It’s how deep they invade into their organ of origin, whether they have spread to distant organs, and how bad they look under the microscope.” The cells of this patient’s tumor are misshapen, haphazardly stacked on top of each other.
The patient is in her forties. Yilmaz recalled that when he was a resident, colon cancer in a 40-year-old or 30-year-old was a rarity. He now sees such cases almost weekly. Colorectal cancer is among the top three leading causes of cancer-related deaths in the United States, according to the American Cancer Society. It’s expected to cause around 53,000 deaths during 2021. Yilmaz writes up his diagnosis: invasive cancer of the sigmoid colon. The patient’s oncologist will consult with Yilmaz, radiologists, and the surgical team to come up with a treatment plan.
Ultimately, Yilmaz wants to develop strategies to prevent and reduce the growth of tumors in the intestinal tract. The fact that increasingly younger patients are being diagnosed highlights, for him, the importance of diet. “It’s very worrisome,” he says. “We’re at the beginning of a trend where we’re going to see more and more young people afflicted with what can be a fatal disease if not caught early.” Diet could be an important place to start.
He says, “If you can prevent cancer, that’s the best treatment.”
Researchers decipher when and why immune cells fail to respond to immunotherapy, suggesting that T cells need a different kind of prodding to re-engage the immune response.
Grace van Deelen
October 29, 2021
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer in humans. Some patients with NSCLC receive a therapy called immune checkpoint blockade (ICB) that helps kill cancer cells by reinvigorating a subset of immune cells called T cells, which are “exhausted” and have stopped working. However, only about 35% of NSCLC patients respond to ICB therapy. Stefani Spranger’s lab at the MIT Department of Biology explores the mechanisms behind this resistance, with the goal of inspiring new therapies to better treat NSCLC patients. In a new study published on Oct. 29 in Science Immunology, a team led by Spranger lab postdoc Brendan Horton revealed what causes T cells to be non-responsive to ICB — and suggested a possible solution.
Scientists have long thought that the conditions within a tumor were responsible for determining when T cells stop working and become exhausted after being overstimulated or working for too long to fight a tumor. That’s why physicians prescribe ICB to treat cancer — ICB can invigorate the exhausted T cells within a tumor. However, Horton’s new experiments show that some ICB-resistant T cells stop working before they even enter the tumor. These T cells are not actually exhausted, but rather they become dysfunctional due to changes in gene expression that arise early during the activation of a T cell, which occurs in lymph nodes. Once activated, T cells differentiate into certain functional states, which are distinguishable by their unique gene expression patterns.
In order to determine why some tumors are resistant to ICB, Horton and the research team studied T cells in murine models of NSCLC. The researchers sequenced messenger RNA from the responsive and non-responsive T cells in order to identify any differences between the T cells. Supported in part by the Koch Institute Frontier Research Program, they used a technique called Seq-Well, developed in the lab of fellow Koch Institute member J. Christopher Love, the Raymond A. (1921) and Helen E. St. Laurent Professor of Chemical Engineering and a co-author of the study. The technique allows for the rapid gene expression profiling of single cells, which permitted Spranger and Horton to get a very granular look at the gene expression patterns of the T cells they were studying.
Seq-Well revealed distinct patterns of gene expression between the responsive and non-responsive T cells. These differences, which are determined when the T cells assume their specialized functional states, may be the underlying cause of ICB resistance.
Now that Horton and his colleagues had a possible explanation for why some T cells did not respond to ICB, they decided to see if they could help the ICB-resistant T cells kill the tumor cells. When analyzing the gene expression patterns of the non-responsive T cells, the researchers had noticed that these T cells had a lower expression of receptors for certain cytokines, small proteins that control immune system activity. To counteract this, the researchers treated lung tumors in murine models with extra cytokines. As a result, the previously non-responsive T cells were then able to fight the tumors — meaning that the cytokine therapy prevented, and potentially even reversed, the dysfunctionality.
Administering cytokine therapy to human patients is not currently safe, because cytokines can cause serious side effects as well as a reaction called a “cytokine storm,” which can produce severe fevers, inflammation, fatigue, and nausea. However, there are ongoing efforts to figure out how to safely administer cytokines to specific tumors. In the future, Spranger and Horton suspect that cytokine therapy could be used in combination with ICB.
“This is potentially something that could be translated into a therapeutic that could increase the therapy response rate in non-small cell lung cancer,” Horton says.
Spranger agrees that this work will help researchers develop more innovative cancer therapies, especially because researchers have historically focused on T cell exhaustion rather than the earlier role that T cell functional states might play in cancer.
“If T cells are rendered dysfunctional early on, ICB is not going to be effective, and we need to think outside the box,” she says. “There’s more evidence, and other labs are now showing this as well, that the functional state of the T cell actually matters quite substantially in cancer therapies.” To Spranger, this means that cytokine therapy “might be a therapeutic avenue” for NSCLC patients beyond ICB.
Jeffrey Bluestone, the A.W. and Mary Margaret Clausen Distinguished Professor of Metabolism and Endocrinology at the University of California-San Francisco, who was not involved with the paper, agrees. “The study provides a potential opportunity to ‘rescue’ immunity in the NSCLC non-responder patients with appropriate combination therapies,” he says.
This research was funded by the Pew-Stewart Scholars for Cancer Research, the Ludwig Center for Molecular Oncology, the Koch Institute Frontier Research Program through the Kathy and Curt Mable Cancer Research Fund, and the National Cancer Institute.
A new study finds cutting off cells’ supplies of lipids can slow the growth of tumors in mice.
Anne Trafton | MIT News Office
October 20, 2021
In recent years, there has been some evidence that dietary interventions can help to slow the growth of tumors. A new study from MIT, which analyzed two different diets in mice, reveals how those diets affect cancer cells, and offers an explanation for why restricting calories may slow tumor growth.
The study examined the effects of a calorically restricted diet and a ketogenic diet in mice with pancreatic tumors. While both of these diets reduce the amount of sugar available to tumors, the researchers found that only the calorically restricted diet reduced the availability of fatty acids, and this was linked to a slowdown in tumor growth.
The findings do not suggest that cancer patients should try to follow either of these diets, the researchers say. Instead, they believe the findings warrant further study to determine how dietary interventions might be combined with existing or emerging drugs to help patients with cancer.
“There’s a lot of evidence that diet can affect how fast your cancer progresses, but this is not a cure,” says Matthew Vander Heiden, director of MIT’s Koch Institute for Integrative Cancer Research and the senior author of the study. “While the findings are provocative, further study is needed, and individual patients should talk to their doctor about the right dietary interventions for their cancer.”
MIT postdoc Evan Lien is the lead author of the paper, which appears today in Nature.
Metabolic mechanism
Vander Heiden, who is also a medical oncologist at Dana-Farber Cancer Institute, says his patients often ask him about the potential benefits of various diets, but there is not enough scientific evidence available to offer any definitive advice. Many of the dietary questions that patients have focus on either a calorie-restricted diet, which reduces calorie consumption by 25 to 50 percent, or a ketogenic diet, which is low in carbohydrates and high in fat and protein.
Previous studies have suggested that a calorically restricted diet might slow tumor growth in some contexts, and such a diet has been shown to extend lifespan in mice and many other animal species. A smaller number of studies exploring the effects of a ketogenic diet on cancer have produced inconclusive results.
“A lot of the advice or cultural fads that are out there aren’t necessarily always based on very good science,” Lien says. “It seemed like there was an opportunity, especially with our understanding of cancer metabolism having evolved so much over the past 10 years or so, that we could take some of the biochemical principles that we’ve learned and apply those concepts to understanding this complex question.”
Cancer cells consume a great deal of glucose, so some scientists had hypothesized that either the ketogenic diet or calorie restriction might slow tumor growth by reducing the amount of glucose available. However, the MIT team’s initial experiments in mice with pancreatic tumors showed that calorie restriction has a much greater effect on tumor growth than the ketogenic diet, so the researchers suspected that glucose levels were not playing a major role in the slowdown.
To dig deeper into the mechanism, the researchers analyzed tumor growth and nutrient concentration in mice with pancreatic tumors, which were fed either a normal, ketogenic, or calorie-restricted diet. In both the ketogenic and calorie-restricted mice, glucose levels went down. In the calorie-restricted mice, lipid levels also went down, but in mice on the ketogenic diet, they went up.
Lipid shortages impair tumor growth because cancer cells need lipids to construct their cell membranes. Normally, when lipids aren’t available in a tissue, cells can make their own. As part of this process, they need to maintain the right balance of saturated and unsaturated fatty acids, which requires an enzyme called stearoyl-CoA desaturase (SCD). This enzyme is responsible for converting saturated fatty acids into unsaturated fatty acids.
Both calorie-restricted and ketogenic diets reduce SCD activity, but mice on the ketogenic diet had lipids available to them from their diet, so they didn’t need to use SCD. Mice on the calorie-restricted diet, however, couldn’t get fatty acids from their diet or produce their own. In these mice, tumor growth slowed significantly, compared to mice on the ketogenic diet.
“Not only does caloric restriction starve tumors of lipids, it also impairs the process that allows them to adapt to it. That combination is really contributing to the inhibition of tumor growth,” Lien says.
Dietary effects
In addition to their mouse research, the researchers also looked at some human data. Working with Brian Wolpin, an oncologist at Dana-Farber Cancer Institute and an author of the paper, the team obtained data from a large cohort study that allowed them to analyze the relationship between dietary patterns and survival times in pancreatic cancer patients. From that study, the researchers found that the type of fat consumed appears to influence how patients on a low-sugar diet fare after a pancreatic cancer diagnosis, although the data are not complete enough to draw any conclusions about the effect of diet, the researchers say.
Although this study showed that calorie restriction has beneficial effects in mice, the researchers say they do not recommend that cancer patients follow a calorie-restricted diet, which is difficult to maintain and can have harmful side effects. However, they believe that cancer cells’ dependence on the availability of unsaturated fatty acids could be exploited to develop drugs that might help slow tumor growth.
One possible therapeutic strategy could be inhibition of the SCD enzyme, which would cut off tumor cells’ ability to produce unsaturated fatty acids.
“The purpose of these studies isn’t necessarily to recommend a diet, but it’s to really understand the underlying biology,” Lien says. “They provide some sense of the mechanisms of how these diets work, and that can lead to rational ideas on how we might mimic those situations for cancer therapy.”
The researchers now plan to study how diets with a variety of fat sources — including plant or animal-based fats with defined differences in saturated, monounsaturated, and polyunsaturated fatty acid content — alter tumor fatty acid metabolism and the ratio of unsaturated to saturated fatty acids.
The research was funded by the Damon Runyon Cancer Research Foundation, the National Institutes of Health, the Lustgarten Foundation, the Dana-Farber Cancer Institute Hale Family Center for Pancreatic Cancer Research, Stand Up to Cancer, the Pancreatic Cancer Action Network, the Noble Effort Fund, the Wexler Family Fund, Promises for Purple, the Bob Parsons Fund, the Emerald Foundation, the Howard Hughes Medical Institute, the MIT Center for Precision Cancer Medicine, and the Ludwig Center at MIT.
By combining chemotherapy, tumor injury, and immunotherapy, researchers show that the immune system can be re-engaged to destroy tumors in mice.
Anne Trafton | MIT News Office
October 20, 2021
Immunotherapy is a promising strategy to treat cancer by stimulating the body’s own immune system to destroy tumor cells, but it only works for a handful of cancers. MIT researchers have now discovered a new way to jump-start the immune system to attack tumors, which they hope could allow immunotherapy to be used against more types of cancer.
Their novel approach involves removing tumor cells from the body, treating them with chemotherapy drugs, and then placing them back in the tumor. When delivered along with drugs that activate T cells, these injured cancer cells appear to act as a distress signal that spurs the T cells into action.
“When you create cells that have DNA damage but are not killed, under certain conditions those live, injured cells can send a signal that awakens the immune system,” says Michael Yaffe, who is a David H. Koch Professor of Science, the director of the MIT Center for Precision Cancer Medicine, and a member of MIT’s Koch Institute for Integrative Cancer Research.
In mouse studies, the researchers found that this treatment could completely eliminate tumors in nearly half of the mice.
Yaffe and Darrell Irvine, who is the Underwood-Prescott Professor with appointments in MIT’s departments of Biological Engineering and Materials Science and Engineering, and an associate director of the Koch Institute, are the senior authors of the study, which appears today in Science Signaling. MIT postdoc Ganapathy Sriram and Lauren Milling PhD ’21 are the lead authors of the paper.
T cell activation
One class of drugs currently used for cancer immunotherapy is checkpoint blockade inhibitors, which take the brakes off of T cells that have become “exhausted” and unable to attack tumors. These drugs have shown success in treating a few types of cancer but do not work against many others.
Yaffe and his colleagues set out to try to improve the performance of these drugs by combining them with cytotoxic chemotherapy drugs, in hopes that the chemotherapy could help stimulate the immune system to kill tumor cells. This approach is based on a phenomenon known as immunogenic cell death, in which dead or dying tumor cells send signals that attract the immune system’s attention.
Several clinical trials combining chemotherapy and immunotherapy drugs are underway, but little is known so far about the best way to combine these two types of treatment.
The MIT team began by treating cancer cells with several different chemotherapy drugs, at different doses. Twenty-four hours after the treatment, the researchers added dendritic cells to each dish, followed 24 hours later by T cells. Then, they measured how well the T cells were able to kill the cancer cells. To their surprise, they found that most of the chemotherapy drugs didn’t help very much. And those that did help appeared to work best at low doses that didn’t kill many cells.
The researchers later realized why this was so: It wasn’t dead tumor cells that were stimulating the immune system; instead, the critical factor was cells that were injured by chemotherapy but still alive.
“This describes a new concept of immunogenic cell injury rather than immunogenic cell death for cancer treatment,” Yaffe says. “We showed that if you treated tumor cells in a dish, when you injected them back directly into the tumor and gave checkpoint blockade inhibitors, the live, injured cells were the ones that reawaken the immune system.”
The drugs that appear to work best with this approach are drugs that cause DNA damage. The researchers found that when DNA damage occurs in tumor cells, it activates cellular pathways that respond to stress. These pathways send out distress signals that provoke T cells to leap into action and destroy not only those injured cells but any tumor cells nearby.
“Our findings fit perfectly with the concept that ‘danger signals’ within cells can talk to the immune system, a theory pioneered by Polly Matzinger at NIH in the 1990s, though still not universally accepted,” Yaffe says.
Tumor elimination
In studies of mice with melanoma and breast tumors, the researchers showed that this treatment eliminated tumors completely in 40 percent of the mice. Furthermore, when the researchers injected cancer cells into these same mice several months later, their T cells recognized them and destroyed them before they could form new tumors.
The researchers also tried injecting DNA-damaging drugs directly into the tumors, instead of treating cells outside the body, but they found this was not effective because the chemotherapy drugs also harmed T cells and other immune cells near the tumor. Also, injecting the injured cells without checkpoint blockade inhibitors had little effect.
“You have to present something that can act as an immunostimulant, but then you also have to release the preexisting block on the immune cells,” Yaffe says.
Yaffe hopes to test this approach in patients whose tumors have not responded to immunotherapy, but more study is needed first to determine which drugs, and at which doses, would be most beneficial for different types of tumors. The researchers are also further investigating the details of exactly how the injured tumor cells stimulate such a strong T cell response.
The research was funded, in part, by the National Institutes of Health, the Mazumdar-Shaw International Oncology Fellowship, the MIT Center for Precision Cancer Medicine, and the Charles and Marjorie Holloway Foundation.
Studying cancer in the Sharp lab helped Courtney JnBaptiste learn strategic thinking skills that he uses as a patent agent, transforming technology into successful biotech businesses.
Raleigh McElvery | Department of Biology
October 17, 2021
Courtney JnBaptiste PhD ’16 spent the first 19 years of his life on the idyllic Caribbean island of Saint Lucia, surrounded by clear waters, sandy beaches, and a robust agricultural community. His family owned their own farm, where they grew bananas and other crops for export. JnBaptiste and his six siblings spent hours each day after school and on the weekends helping to harvest the fruits of their labor. “We were better off than most, but it was a hard existence,” he says. “I had to fight to make something out of life. Where I am today is a big leap.”
He has since moved to the U.S. and completed his PhD at the MIT Department of Biology. Today, he uses the strategic thinking skills he learned during graduate school in his job as a patent agent, helping researchers protect their inventions and start biotech companies.
Despite his exceptional grades, JnBaptiste didn’t enjoy school growing up, and he’d often try to convince his parents that he didn’t need to go to class. His mother, a middle school teacher, was unfazed by his excuses and sent him off to school most days. Despite his protests, JnBaptiste understood his mother’s motto that “education is the key to success.” He knew he’d need good academic standing and self-motivation to attain the financially-stable life he envisioned.
During high school, cable TV became available to his community for the first time, and he was overwhelmed by the deluge of information. He became hooked on Animal Planet and Discovery Channel, and decided that he wanted to be like Jeff Corwin, a biologist, wildlife conservationist, and TV personality. JnBaptiste knew he’d need a college education to reach his career aspirations, and — due to its proximity and promise of opportunity — the U.S. seemed like an ideal destination.
He was accepted to Bethune-Cookman University in Florida and declared a major in biology. He was awarded an environmental research grant, which allowed him to spend several semesters studying the snail populations in Blue Spring State Park. But a summer internship at the University of Kansas Medical Center was what ultimately convinced him to pursue molecular biology rather than environmental sciences. During his junior year, a new biochemistry professor arrived: Christopher Ainsley Davis, a former postdoc in the lab of Cathy Drennan at the MIT Department of Biology.
“When the two of us spoke, he said something that shocked me,” JnBaptiste recalls. “He told me, ‘You’re good enough for MIT and you should apply to their summer research program.’ That just blew my mind. I never thought I was of the MIT caliber — no one had ever challenged me like that before.”
At Davis’ urging, JnBaptiste applied to the MIT Summer Research Program in Biology (MSRP-Bio), and was placed in the lab of Nobel laureate Phil Sharp. In the 1970s, Sharp had co-discovered splicing, a molecular process that happens after DNA has been transcribed into RNA. Segments of the RNA strand are removed, and the remaining parts are stitched back together and translated into proteins that perform vital functions inside the cell.
Under the supervision of graduate student and postdoc mentors, JnBaptiste spent the summer of 2009 investigating the role that RNA splicing plays in cancer. “It was the best time of my life,” he says. “I just I loved it. I loved the environment. I loved the lab. I loved MIT. And that experience had a profound impact on me.”
He enjoyed campus so much that he returned just one year later to begin his PhD. He was looking forward to returning to the lab bench, but what he didn’t anticipate was that his first semester of classes would be the most rigorous education he’d ever received. He excelled in biochemistry, but found 7.52 (Graduate Genetics) especially difficult. “It was the first time I’d ever failed an exam,” he recalls.
With the help of mentors, classmates, and tutors, JnBaptiste passed genetics and moved on to the stage of his PhD that he was most excited about: lab rotations. After testing out a few different research groups, he ultimately decided to return to the Sharp lab. In his own words: “It was home.”
JnBaptiste’s thesis project focused on a type of RNA known as microRNA (miRNA), which is never translated into a protein. Instead, it remains in its single-stranded RNA form and helps regulate gene expression. The Sharp lab found that removing all the miRNAs from adult cells prompted dramatic activation of embryonic genes. These genes are typically turned off in adult cells, and only expressed during early development when rapid cell division is required. But they can also be hijacked during cancer to create tumors.
JnBaptiste was surprised to find that adding the miRNAs back into the cells didn’t shut down these embryonic genes. In fact, restoring the miRNAs made the cells divide even more rapidly and increased their ability to form tumors — suggesting “global miRNA restoration” would not be a viable approach to treat cancer.
“This model that we developed showed miRNAs control a very important network in the context of both development and cancer,” JnBaptiste explains. “Cancer occurs when normal cellular processes go awry, so understanding those fundamental molecular interactions is critical to fighting the disease.”
By the time he graduated from MIT in 2016, JnBaptiste knew he enjoyed science, but didn’t have ambitions to run his own lab. Instead, he was curious about how lab experiments and research questions engender companies.
When he was still an MSRP-Bio student, JnBaptiste had met an intellectual property lawyer who’d come to speak on campus. He’d been saving her business card ever since, and reached out to her as his time at MIT was drawing to a close. With her assistance, JnBaptiste was offered a job as a scientific advisor at Goodwin Procter, the international law firm where she worked.
JnBaptiste has since transitioned to a similar role as a patent agent at Pabst Patent Group. There, he collaborates with lawyers to write patents protecting new research technology. While scientists are focused on the minutia of their day-to-day lab experiments, JnBaptiste is tasked with understanding the bigger picture, and how those experiments might lay the foundation for successful businesses that could revolutionize therapeutic approaches.
“As a grad student at MIT, I learned a lot about what it takes to be a strategic thinker in science,” JnBaptiste says. “People like my mentor, Phil Sharp, not only recognize a discovery, they look beyond it to envision its future potential as the next biotech company. That’s a skill I’m still honing as I work to develop my business acumen.”
Looking back at his career trajectory thus far, JnBaptiste is struck by the “beauty and diversity” that comes with earning a degree in biology. “Follow your passions,” he advises, “and surround yourself with people who can see the potential and value in you — even when you cannot yet see it yourself.”
Posted: 10.17.21
Top photo: Elisabeth Sherwin/Hello Headshots
Vaccinating against certain proteins found on cancer cells could help to enhance the T cell response to tumors.
Anne Trafton | MIT News Office
September 16, 2021
Over the past decade, scientists have been exploring vaccination as a way to help fight cancer. These experimental cancer vaccines are designed to stimulate the body’s own immune system to destroy a tumor, by injecting fragments of cancer proteins found on the tumor.
So far, none of these vaccines have been approved by the FDA, but some have shown promise in clinical trials to treat melanoma and some types of lung cancer. In a new finding that may help researchers decide what proteins to include in cancer vaccines, MIT researchers have found that vaccinating against certain cancer proteins can boost the overall T cell response and help to shrink tumors in mice.
The research team found that vaccinating against the types of proteins they identified can help to reawaken dormant T cell populations that target those proteins, strengthening the overall immune response.
“This study highlights the importance of exploring the details of immune responses against cancer deeply. We can now see that not all anticancer immune responses are created equal, and that vaccination can unleash a potent response against a target that was otherwise effectively ignored,” says Tyler Jacks, the David H. Koch Professor of Biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.
MIT postdoc Megan Burger is the lead author of the new study, which appears today in Cell.
T cell competition
When cells begin to turn cancerous, they start producing mutated proteins not seen in healthy cells. These cancerous proteins, also called neoantigens, can alert the body’s immune system that something has gone wrong, and T cells that recognize those neoantigens start destroying the cancerous cells.
Eventually, these T cells experience a phenomenon known as “T cell exhaustion,” which occurs when the tumor creates an immunosuppressive environment that disables the T cells, allowing the tumor to grow unchecked.
Scientists hope that cancer vaccines could help to rejuvenate those T cells and help them to attack tumors. In recent years, they have worked to develop methods for identifying neoantigens in patient tumors to incorporate into personalized cancer vaccines. Some of these vaccines have shown promise in clinical trials to treat melanoma and non-small cell lung cancer.
“These therapies work amazingly in a subset of patients, but the vast majority still don’t respond very well,” Burger says. “A lot of the research in our lab is aimed at trying to understand why that is and what we can do therapeutically to get more of those patients responding.”
Previous studies have shown that of the hundreds of neoantigens found in most tumors, only a small number generate a T cell response.
The new MIT study helps to shed light on why that is. In studies of mice with lung tumors, the researchers found that as tumor-targeting T cells arise, subsets of T cells that target different cancerous proteins compete with each other, eventually leading to the emergence of one dominant population of T cells. After these T cells become exhausted, they still remain in the environment and suppress any competing T cell populations that target different proteins found on the tumor.
However, Burger found that if she vaccinated these mice with one of the neoantigens targeted by the suppressed T cells, she could rejuvenate those T cell populations.
“If you vaccinate against antigens that have suppressed responses, you can unleash those T cell responses,” she says. “Trying to identify these suppressed responses and specifically targeting them might improve patient responses to vaccine therapies.”
Shrinking tumors
In this study, the researchers found that they had the most success when vaccinating with neoantigens that bind weakly to immune cells that are responsible for presenting the antigen to T cells. When they used one of those neoantigens to vaccinate mice with lung tumors, they found the tumors shrank by an average of 27 percent.
“The T cells proliferate more, they target the tumors better, and we see an overall decrease in lung tumor burden in our mouse model as a result of the therapy,” Burger says.
After vaccination, the T cell population included a type of cells that have the potential to continuously refuel the response, which could allow for long-term control of a tumor.
In future work, the researchers hope to test therapeutic approaches that would combine this vaccination strategy with cancer drugs called checkpoint inhibitors, which can take the brakes off exhausted T cells, stimulating them to attack tumors. Supporting that approach, the results published today also indicate that vaccination boosts the number of a specific type of T cells that have been shown to respond well to checkpoint therapies.
The research was funded by the Howard Hughes Medical Institute, the Ludwig Center at Harvard University, the National Institutes of Health, the Koch Institute Support (core) Grant from the National Cancer Institute, the Bridge Project of the Koch Institute and Dana-Farber/Harvard Cancer Center, and fellowship awards from the Jane Coffin Childs Memorial Fund for Medical Research and the Ludwig Center for Molecular Oncology at MIT.
Researchers find three immunotherapy drugs given together can eliminate pancreatic tumors in mice.
Anne Trafton | MIT News Office
August 5, 2021
Pancreatic cancer, which affects about 60,000 Americans every year, is one of the deadliest forms of cancer. After diagnosis, fewer than 10 percent of patients survive for five years.
While some chemotherapies are initially effective, pancreatic tumors often become resistant to them. The disease has also proven difficult to treat with newer approaches such as immunotherapy. However, a team of MIT researchers has now developed an immunotherapy strategy and shown that it can eliminate pancreatic tumors in mice.
The new therapy, which is a combination of three drugs that help boost the body’s own immune defenses against tumors, is expected to enter clinical trials later this year.
“We don’t have a lot of good options for treating pancreatic cancer. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it would make a big impact in at least a subset of patients’ lives, but we need to see how it will actually perform in trials.”
Freed-Pastor, who is also a medical oncologist at Dana-Farber Cancer Institute, is the lead author of the new study, which appears today in Cancer Cell. Tyler Jacks, the David H. Koch Professor of Biology and a member of the Koch Institute, is the paper’s senior author.
Immune attack
The body’s immune system contains T cells that can recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that disables these T cells, helping the tumor to survive.
Immune checkpoint therapy (the most common form of immunotherapy currently being used clinically) works by removing the brakes on these T cells, rejuvenating them so they can destroy tumors. One class of immunotherapy drug that has shown success in treating many types of cancer targets the interactions between PD-L1, a cancer-linked protein that turns off T cells, and PD-1, the T cell protein that PD-L1 binds to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, have been approved to treat cancers such as melanoma and lung cancer, but they have very little effect on pancreatic tumors.
Some researchers had hypothesized that this failure could be due to the possibility that pancreatic tumors don’t express as many cancerous proteins, known as neoantigens. This would give T cells fewer targets to attack, so that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be able to identify and destroy tumor cells.
However, some recent studies had shown, and the new MIT study confirmed, that many pancreatic tumors do in fact express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients.
In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Instead, most pancreatic cancer cells express a protein called CD155, which activates a receptor on T cells known as TIGIT.
When TIGIT is activated, the T cells enter a state known as “T cell exhaustion,” in which they are unable to mount an attack on pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, the researchers observed TIGIT expression and T cell exhaustion from about 60 percent of patients, and they also found high levels of CD155 on tumor cells from patients.
“The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells,” Freed-Pastor says. “When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”
Drug combination
The researchers then set out to see if they could use this knowledge to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. They tested a variety of combinations of experimental drugs that inhibit PD-1 and TIGIT, along with another type of drug called a CD40 agonist antibody.
CD40 agonist antibodies, some of which are currently being clinically evaluated to treat pancreatic cancer, are drugs that activate T cells and drive them into tumors. In tests in mice, the MIT team found that drugs against PD-1 had little effect on their own, as has previously been shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was able to halt tumor growth in some animals, but did not substantially shrink tumors.
However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals given this treatment, and in 25 percent of the mice, the tumors disappeared completely. Furthermore, the tumors did not regrow after the treatment was stopped. “We were obviously quite excited about that,” Freed-Pastor says.
Working with the Lustgarten Foundation for Pancreatic Cancer Research, which helped to fund this study, the MIT team sought out two pharmaceutical companies who between them have a PD-1 inhibitor, TIGIT inhibitor, and CD40 agonist antibody in development. None of these drugs are FDA-approved yet, but they have each reached phase 2 clinical trials. A clinical trial on the triple combination is expected to begin later this year.
“This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease,” Jacks says. “We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research.”
Alongside the clinical trial, the MIT team plans to analyze which types of pancreatic tumors might respond best to this drug combination. They are also doing further animal studies to see if they can boost the treatment’s effectiveness beyond the 50 percent that they saw in this study.
In addition to the Lustgarten Foundation, the research was funded by Stand Up To Cancer, the Howard Hughes Medical Institute, Dana-Farber/Harvard Cancer Center, the Damon Runyon Cancer Research Foundation, and the National Institutes of Health.
Education
- PhD, 2015, Johns Hopkins University School of Medicine
- BA, 2009, Molecular Biology & Biochemistry/Physics, Wesleyan University
Research Summary
We investigate crosstalk between CD8+ T cells and their environment at a molecular level, by dissecting the biological and metabolic programs engaged under conditions of stress. Using an array of approaches to model and perturb the local microenvironment, our research aims to reveal both the adaptive molecular changes as well as intrinsic vulnerabilities in T cells that arise within the tumor niche. Our goal is to understand how disease states remodel the fundamental mechanisms that regulate immune cell function and contribute to pathogenesis.
Awards
- Forbeck Scholar, 2021
Education
- PhD, 2016, MIT
- BS, 2008, Chemistry, University of Puerto Rico-Mayagüez
Research Summary
We study chromatin — the complex of DNA and proteins that make up our chromosomes. We aim to understand how post-translational modifications to these building-blocks, as well as the factors that regulate these events, play essential roles in maintaining the integrity of cells, tissues, and ultimately entire organisms. We implement a combination of functional genomics, biochemical, genetic, and epigenomic approaches to study how chromatin and epigenetic factors decode the chemical language of chromatin, and how these are dysregulated in diseases such as cancer.
Awards
- AACR Gertrude B. Elion Cancer Research Award, 2023
- V Foundation Award, 2022
- NIH MOSAIC K99/R00 Postdoctoral Career Transition Award, 2021
- Eddie Méndez Scholar Award, Fred Hutchinson Cancer Research Center, 2020
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Damon Runyon-Sohn Pediatric Cancer Fellowship, Damon Runyon Cancer Research Foundation, 2017