Arlene Sharpe, MD, PhD, is a leader in the field of immunology. Her lab discovered and illuminated the functions of T cell co-stimulatory pathways, crucial players in the development of the body’s immune response. Her work helped lay the groundwork for cancer immunotherapies, including PD1 and CTLA-4 checkpoint inhibitors, in use in the clinic today. Sharpe’s lab is currently exploring how the immune system uses inhibitory signals to regulate T cell activation, tolerance, anti-microbial immunity and cancer. Their goal is to find ways to uncouple the undesirable side effects of cancer immunotherapy—including inflammation and auto-immune adverse events—from its cancer-eradicating benefits.
Sharpe is a member of the Department of Pathology and is also co-director of the Evergrande Center for Immunologic Diseases at Harvard Medical School (HMS) and the Brigham. She is also affiliated with the Broad Institute, the Dana-Farber/Harvard Cancer Center and serves as the George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology at HMS.
Sharpe recently sat down with Brigham Clinical & Research News to share her insights about advancements in the field and the importance of mentorship and collaboration.
Q: What is it like to be an investigator in the field of immunology today?
AS: This is a special time to be in the field. In many ways, immunology, understanding how the immune system is regulated, is at the forefront of medicine. Traditionally, people have thought about the immune system as defending us against microbes, which, of course, it does. But we also know that when it comes to autoimmunity and allergic inflammation, there’s an epidemic. And we don’t understand why. Immunology is critical in understanding those diseases as well as cancer and transplant rejection, a field in which the Brigham is one of the world’s leaders.
But in addition to that, what we’re beginning to appreciate is that many diseases that weren’t thought to have an immune component actually do. Atherosclerosis, obesity and neurodegenerative diseases are just a few examples. Transcriptomics [the study of the complete set of RNA transcripts produced in different cells and circumstances] is revealing that the immune system is involved in a variety of different contexts. It’s exciting to study this from a basic research perspective, but it’s also exciting to talk to clinicians. We’re studying patient samples to understand the commonalities and differences across inflammatory diseases.
Immunology is very appealing as a basic scientist and what we learn can impact patient care and therapy. And it doesn’t get any better than that.
You serve as co-director of the Evergrande Center for Immunologic Diseases, a joint center between HMS and the Brigham. What is the mission of the center?
AS: I’m thrilled to participate in the Evergrande Center. The overall goal of the Evergrande Center is to elucidate mechanisms of chronic inflammation underlying human disease and apply this knowledge to treat those suffering from these diseases. It’s a wonderful vision to take this environment and bring people together in innovative ways. We have, for example, a flagship project on colorectal cancer that brings together basic scientists, immunologists, computational biologists, cancer biologists as well as clinicians, including surgeons, pathologists and oncologists all to work together to build a pipeline for looking at tissue from patients and doing single-cell transcriptomics to try to understand this disease.
To illustrate how the center works, let me give you an example of a project we’ve taken on. There’s a huge unmet need in colorectal cancer. Unfortunately, it’s a cancer that doesn’t respond well to checkpoint blockade. What we’re trying to do is understand what’s different about this tumor microenvironment. And we’re working with experts from across the Harvard ecosystem to do so—it’s real team science.
Q: You’ve been connected to the Pathology Department at the Brigham for many years. How has the department evolved or changed? How has it stayed the same?
AS: There’s a strong tradition of academic pathology in terms of teaching and research as well as clinical service. That’s one of the things that distinguishes the department. That’s been a constant. Although some things and people have changed, the values are definitely the same.
Q: Can you describe your path to the Brigham and HMS?
AS: I came to Boston as an undergraduate and after my sophomore year, I worked in the lab of Jack Strominger, PhD, at Harvard. That was my first experience with science in the university setting. I couldn’t believe they paid people to do this because it was so much fun. I was excited by discovery.
I then went on to graduate with an MD/PhD from HMS, did my graduate work in the lab of Bernard (Bernie) Fields, MD, and became very interested in viral immunology and viral pathogenesis. My thesis work was on reovirus pathogenesis. That led me to do a residency in Pathology at the Brigham when Ramzi Cotran, MD, was the chair.
Q: You’ve had some amazing mentors over the years. How have they shaped your career and your view of mentoring today?
AS: When you have mentors like that, it gives someone who is just starting out confidence in themselves. I feel very fortunate indeed.
In addition, I had “neighbors”—researchers in the lab next door, colleagues in the division—who were amazing as well. All of us pay it forward. Several us who experienced that environment read each other’s grants, give each other feedback and have formed collaborations. Vijay Kuchroo, DVM, PhD, the founding director of the Evergrande Center and an investigator at the Brigham) and I began to collaborate when we were assistant professors. It’s wonderful to continue that collaboration years later. It’s very special.
Today, teaching and mentoring are near and dear to my heart. And we are all mentors. I try to give opportunities to my graduate students to mentor undergraduates, and likewise for postdocs to mentor graduate students and work with technicians. Mentoring and being mentored is important at every level.
You helped make some of the seminal discoveries that have led to the use of checkpoint inhibitors in the clinic. What is it like to have been involved in the discoveries that have led to this point?
AS: It’s been such a thrill. To hear the stories of patients who have benefited from checkpoint inhibitors and are now, several years later, riding their bicycles from Wellesley into Boston for checkups, is just incredible. And this is just the beginning. When you see that type of benefit and realize that we still have a long way to go, I think it makes us work even harder.
I also think the stories of PD1 and CTLA4 illustrate the importance of asking fundamental questions about how the immune system is regulated and the value of investing in basic science research. One of the other things that’s special about the research environment here is that it brings people together at the interface of fields. That’s often something that catalyzes innovation, and this is a perfect environment for doing exactly that.