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Our research, published in the Journal of the Endocrine Society, explores how understanding differences in men’s and women’s immune systems can pave the way for more personalized care.
There’s a puzzling contradiction in thyroid cancer: The condition is three times more common in female patients than in males. Although less common in men, the disease tends to be more aggressive when it does occur.
Doctors have known about this “sex dimorphism” for decades, but treatment approaches haven’t changed much to reflect it. Our research, published in the Journal of the Endocrine Society, aimed to examine why these differences might exist.
To provide the best, most personalized care, it’s critical to stop treating every patient as “average.” Instead, we should work to understand each person’s unique biology.
By exploring how the immune system behaves differently in men and women, we’re contributing to a new era of precision medicine, in which treatments can be as unique as an individual’s biology.
Personalizing the reference standard for thyroid cancer.
For a long time, our understanding of basic science has been built on a narrow foundation. Many of the standards used to interpret test results, known as reference values, were originally based on studies of predominantly white male populations. Using this limited view of what’s “normal” biases how we understand what’s healthy.
Biological sex is one of the most fundamental differences between humans. It affects everything from our hormones to how our individual cells function. When we ignore these differences, we risk creating treatments that are less effective for some people or that cause more side effects among certain groups.
Our research focuses on differentiated thyroid cancer (DTC), the most common type of the disease. The goal was to move beyond these outdated standards to ensure that every patient’s care is grounded in how their specific body fights cancer.
Related: Read “Beyond Diagnosis: What Research Reveals About Genetic Testing and Your Family’s Cancer Risk.”
Mapping the immune system neighborhood.
To understand why DTC behaves differently in men and women, we studied the tumor immune microenvironment. This is like the neighborhood surrounding the tumor. Some neighbors help the body fight cancer, while others help hide it from the immune system.
To study this, we used blood and tissue samples from patients with differentiated thyroid cancer at MedStar Washington Hospital Center. We analyzed these samples using two advanced tools:
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Flow cytometry: Flow cytometry tells us who is in the neighborhood. This high-speed scanner allows us to take a sample of cells from thyroid cancer and examine them one by one. The device identifies and counts each cell based on its markers, allowing us to determine which immune cell types are present.
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RNA sequencing and spatial transcriptomics help us understand what those cells are doing. By measuring gene activity within cells, we can determine whether immune cells are actively fighting the tumor or have been “turned off” by it. Spatial transcriptomics also help us understand where these cells are located within the tumor.
Using these tools together, we discovered that the tumor environment/”neighborhood” differs significantly between male and female patients.
The exhausted immune system in men.
One of our most striking findings was that the tumor microenvironment is typically more immunosuppressive in men than in women. This means that cancer has found a way to flip a switch that turns off the body’s natural defenses as the tumor grows. This leads to what scientists call “immune exhaustion” - a state in which immune cells become worn out and lose their ability to fight cancer effectively.
We found higher levels of exhaustion markers, such as TIGIT and LAG3, in T cells from male patients. In a healthy body, T-cells act as the immune system’s security to defend against invaders. But when these cells become exhausted, they lose both the strength and the signals needed to attack tumor cells.
This high level of immune exhaustion at the site of the tumor in men may help explain why thyroid cancer often behaves more aggressively in men and suggests that therapies aimed at “reawakening” these immune cells could be especially beneficial in men.
Natural killer cells: The body’s specialized guards.
We also studied natural killer (NK) cells. These are specialized immune cells that act like an elite security team. They patrol the body and are recruited to tumor sites to destroy cancer cells before they can spread.
But just having NK cells isn’t enough; these cells must be “mature” to function effectively. Our study found a few key differences in the NK cells of men and women with thyroid cancer:
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Female patients tended to have a higher number of mature, ready-to-function NK cells.
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Male patients had a higher proportion of immature NK cells that were less effective at killing cancer cells.
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The hormone estradiol, which is higher in premenopausal women, may help support NK cell maturation and activity.
This research suggests that hormonal differences may contribute to how effectively the immune system controls thyroid cancer. In men and potentially in women after menopause (when estradiol levels are low) this protective effect may be reduced.
While these findings provide important insights, further studies are needed to confirm how these immune differences directly influence treatment outcomes.
Related: Read “How is Immunotherapy Used to Treat Cancer?”
Collaborating for success.
This research involved significant collaboration throughout the process. This work was possible thanks to the partnership of several experts and institutions, including:
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MedStar Washington Hospital Center Departments of Medicine and Surgery
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The National Institutes of Health, specifically the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Allergy and Infectious Diseases
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Georgetown University Medical Center’s Innovation Center for Biomedical Informatics
I’m deeply grateful for the mentorship Kenneth Burman, MD, Leonard Wartofsky, MD, and Michael Atkins, MD as well as the support of Vasyl Vasko, MD, Joanna Klubo-Gwiezdzinska, MD, Jennifer Rosen, MD, and many other dedicated colleagues. We advance science through collective effort to solve complex problems for our patients.
I am also grateful for the generous support we received from the following sources which made our work possible:
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MedStar Health Research Institute
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American Thyroid Association
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Schneider and Heron’s Vanguard Charitable Fund
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The Trustees of the Charles & Mary Latham Fund
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Wilkoff’s Family Fund
The future of precision medicine.
These exciting results are just the beginning of our work. By identifying sex-specific differences in the immune system, we can begin to design clinical trials to test more precise, targeted immune therapies.
We’re driving toward a future where a patient’s biological sex and hormonal status are standard considerations in their treatment plan. This is the heart of precision medicine: moving away from a world in which we treat a disease, and toward one in which we treat a unique person.
