When Miriam Merad arrived on Stanford University’s campus in 1997, she already had a medical degree from the University of Algiers and a master’s degree in biotechnology from the University of Paris. She came to California from France to work in Edgar Engleman’s pathology laboratory and earn a graduate degree in immunology. Merad had read a paper coauthored by Engleman and Stanford colleague Ronald Levy that described the first clinical trial of a therapeutic vaccine, derived from cancer patients’ own cells, to treat lymphoma. The cancer vaccine field was just getting started, and Merad wanted to be part of it.
She had come to Stanford with the intention of eventually returning to France to take a position in which she could see patients and do research. But her experience in Engelman’s lab made her reconsider. “It was an extraordinary time for me that changed my mind,” Merad recalls. She had been used to focusing on patient care and doing research on the side. “As a resident, you work like hell, and every experiment I did was when I could steal a little bit of time,” she explains. “And here I was at Stanford, with access to the best technology tools and scientists, and I was free to focus all of my time on just the science.”
In Engleman’s lab, Merad was working with dendritic cells—immune system cells that identify foreign antigens and alert T cells to home in on invading pathogens or cancer cells expressing those antigens. In her experiments, Merad extracted mouse dendritic cells, cultured them, activated them by exposing them to tumor-specific antigens, and injected them into the skin of mice with tumors to see if the cells would elicit a T-cell response. These experiments were similar to those used to derive patient-based dendritic cell cancer vaccines.
Merad began to wonder how skin and other tissues where dendritic cells reside would react to the introduction of these cells. The dogma in the field had been that all immune cells, including dendritic cells, were constantly being renewed by blood stem cells in the bone marrow. To test this idea, Merad focused on Langerhans cells, a type of dendritic cell that resides in the skin. She irradiated mice to rid them of their blood stem cells, then infused them with labeled donor bone marrow stem cells and tracked these cells’ differentiation into dendritic cells. The donor cells repopulated 90 percent of all dendritic cells normally found in the spleen, liver, and kidneys. But the donor cells didn’t repopulate many of the Langerhans cells in the skin. Less than 3 percent came from the donor cells both 8 weeks and 18 months after the transplantation, she reported in a 2002 Nature Immunology paper. “This was the first demonstration that tissue-resident dendritic cells can persist throughout life, independent of adult hematopoiesis,” Merad says. She later showed that Langerhans cells belong to the macrophage lineage and that many macrophages share Langerhans cell properties.
The work was incredibly influential in immunology: it showed for the first time that Langerhans cells do not normally arise from adult precursor cells that travel through the blood to various tissues. Instead, the skin-based dendritic cells come from embryonic precursor cells, which migrate to the skin and are renewed and maintained there throughout life, recruiting reinforcements from blood-borne precursors only under conditions of severe inflammation. That finding had profound implications for developing immunotherapies. “By propagating the dendritic cells in vitro, we had been ignorant of the tissue characteristics of these cells, and missing their important biology,” Merad says.
The idea that you can use immune cells and get rid of cancer was somehow magical.
Following this study, Merad had a hunch that the dendritic cell vaccine developed by Engleman and Levy was not very potent because the therapeutic cells generated in petri dishes were not capturing all the important properties of their in-vivo counterparts. Merad and her colleagues demonstrated that rather than generating these cells in vitro, the team could use growth factors to expand and activate them in the body. Expressing a signaling peptide called macrophage inflammatory protein-3α in tumors in the skin of mice, for example, attracted circulating dendritic cells into the tumors. Merad, who is now at Mount Sinai in New York, and many others are currently studying this technique to expand dendritic cells to combat melanoma and lymphoma.
For the public good
Merad was born in 1969 in Paris, where her parents, Rachida and Karim, were completing their medical studies. The family moved back home to Algeria two years later, and her father, a cardiologist, and mother, a toxicologist, took up the roles that so many native Algerians did after the country gained its independence from France in 1962—working to rebuild and populate its civil and medical positions with educated natives. “After about 100 years of rule by the French, they suddenly all left, leaving hospitals without doctors. It was a chaotic time,” Merad says. Her parents were among those who sought to serve the public, and they helped reestablish the medical system in Algeria. Her mother was instrumental in building the first anti-poison center in Africa. “It was a remarkable time, and it gave me a sense of serving larger causes,” Merad says. With her parents working long hours, she and her three brothers and sisters made the hospital a second home. Merad also affirmed her career aspiration: going into medicine and caring for patients.
As a child, Merad was a good student, excelling in science and physics. In high school, she and a few friends formed an informal physics club, tackling challenging math and physics concepts with the guidance of a teacher. After graduating from high school two years early because she had skipped two grades, Merad directly entered a six-year medical school program at the University of Algiers in 1985. Her final two years of med school were spent in France, after she took an exam to win a spot in an internship program that placed only the top 2 percent of students in hospitals in France and Algeria. “It was the most academically challenging thing I’ve done in my life,” Merad recalls. Her hard work paid off, and she earned a residency position at the Hospital of Paris, among the most coveted residency programs in France.
Inspired by a friend of her father who was building a pediatric bone marrow transplant program in Algeria, Merad chose a hematology-oncology focus. She also heard about E. Donnall Thomas, of the Fred Hutchinson Cancer Research Center, who had received the Nobel Prize in Medicine as the pioneer of bone marrow and blood stem cell transplantation. “I realized that transplants—and the immune system—can be used to treat and cure cancer,” Merad recalls. “The idea that you can use immune cells and get rid of cancer was somehow magical.”
As a medical resident, Merad enjoyed being with and caring for patients, but then she “met a woman who changed my life,” she says. That woman was Laurence Zitvogel, a cancer immunologist who was working on cancer vaccines using dendritic cells at the Gustave Roussy Institute of Oncology in Paris. “She was doing cutting-edge research and was very inspiring and passionate,” Merad says. “She exposed me to the magic of dendritic cell vaccines, tumor immunity, and through her I realized, that I wanted to study cancer immunology.” Merad worked in Zitvogel’s lab, using patients’ blood samples to study the effects of immunotherapy on their circulating dendritic cells.
In parallel with her research in Zitvogel’s lab, Merad was also watching cancer patients’ chemotherapy treatments and was dismayed by the process. “It became clear to me that if you wanted to clear lesions, you had to enlist the immune system to attack tumors,” she says. Encouraged by Zitvogel, Merad decided to pursue a PhD to understand the interplay between tumors and the immune system.
Merad then attended Stanford. There she discovered that epidermal Langerhans cells, which at that time represented the prototype dendritic cells, were maintained in tissues independently of adult hematopoiesis. She also found that in mice receiving a donor bone marrow transplant, Langerhans cells contribute to skin graft-versus-host disease, a condition that arises when donor cells attack host tissues and organs. Prior to the repopulation of the bone marrow with healthy donor stem cells, the bone marrow stem cells of the patient, and in this case the mice, are killed off. But Merad found that the Langerhans cells remain, despite the cytotoxic therapy. Depleting the Langerhans cells prior to transplantation, she found, could prevent graft-versus-host disease. Meanwhile, she met her husband, fellow Algerian Bachir Taouli. He had been training as a radiologist at the University of California, San Francisco, while Merad did her work at Stanford.
At the end of her PhD, Merad was invited to give a talk in Ralph Steinman’s immunology lab at Rockefeller University in New York City. Steinman encouraged her to build her own lab and, she says, gave her the push to pursue an academic career as a professor in the US. She was hired by Mount Sinai Health System and started her own laboratory in January 2004. Taouli joined NYU as a clinical radiologist. The couple’s first son, Zachary, was born in December of the same year. “Setting up my lab was a time of much anxiety, but somehow having a child balanced things out and provided a perspective on my work,” Merad says.
There are so many tools we can use now, building on the knowledge that we have already. It’s really a great time for tumor immunology.
Merad’s lab quickly began to make contributions to the dendritic cell field but also started to work on macrophages, a group of cells related to dendritic cells. Intrigued by her findings that Langerhans cells are maintained independent of adult hematopoiesis, she started to search for the origin of Langerhans cells and whether this property also extended to other dendritic cell or macrophage populations.
The researchers focused on microglia, the macrophages that maintain homeostasis and defend against invaders in the central nervous system. When dysregulated, microglia are associated with neurodegenerative diseases. In 2010, Florent Ginhoux, then a postdoc in Merad’s lab, used genetically labeled embryonic blood progenitors (also called primitive hematopoietic precursors) to track their differentiation into microglia in vivo. The study, published in Science, revealed for the first time that microglia arise from primitive progenitor cells that take up residence in tissues early in prenatal development and are able to maintain the microglial pool in tissue throughout life. “This paper changed the view of macrophage biology,” Merad says. She and her colleagues also showed that in addition to microglia, several other macrophage populations in tissues also originate during embryonic development and can replenish their own numbers locally. The researchers also reclassified Langerhans cells as macrophages, as they shared the same origin as other macrophages.
Her basic science work feeds into Merad’s goal of improving cancer immunotherapy strategies, and to do this, she works closely with clinician-scientists at Mount Sinai. Following a 2009 paper that identified a novel subset of CD103-expressing dendritic cells, Merad’s lab, in collaboration with Joshua Brody’s Mount Sinai lab, showed in 2016 that these cells, at the tumor site in a melanoma mouse model, are instrumental for a robust response to an anti-PD1 immune checkpoint cancer treatment. “This study demonstrated that without these dendritic cells, you can’t have a good response to the immune checkpoint antibody therapy,” Merad says. “There is a lot of interest in targeting these CD103+ cells for therapy development.”
Also in 2016, Merad became head of the Precision Immunology Institute at the Icahn School of Medicine (PrIISM), which encompasses 42 labs, to continue to lead initiatives to enhance immunotherapy in diseases beyond cancer, including inflammatory and autoimmune disorders, Alzheimer’s disease, and cardiovascular issues.
Researchers in her lab, however, remain focused on the role dendritic cells and macrophages play within the tumor microenvironment and on how tumors prevent the normal anti-tumor functions of these cells. Merad is also collaborating with Mount Sinai’s surgeons, to define at the single-cell level the immune microenvironment of tumor lesions. Clinicians supply her with surgical lung and liver samples, and she and her colleagues use single-cell sequencing to determine defects in the dendritic cells and macrophages that populate the tumors. “Identifying how to restore dendritic cell and macrophage antitumor potential can transform cancer immunotherapy strategies,” Merad says.
In 2017, her lab, along with Adeeb Rahman, director of technology development for the Human Immune Monitoring Center at Mount Sinai, was the first to use single-cell analysis—on early lung adenocarcinoma—to map a tumor’s immune-cell landscape. And with Brian Brown, a molecular biologist and gene therapy researcher at Mount Sinai, Merad is developing a CRISPR-based screen using protein barcodes to identify genes that can enhance tumor immunity. “There are so many tools we can use now, building on the knowledge that we have already,” Merad says. “It’s really a great time for tumor immunology.”