Current Research Projects

Our work focuses on the balance of immune activation and immune tolerance. We study how autoimmunity arises from loss of tolerance or inhibition of natural regulatory pathways or checkpoints. On the other side, we try to leverage immune responses and reverse tolerance to improve anti-tumor immunity. As a physician scientist, my research seeks to address the most pressing clinical questions and evolves with the needs of our patients. Here are some of our current projects.

Immune checkpoint inhibitor associated autoimmunity
- Immune related adverse events (IrAEs)

Checkpoint inhibitors, including anti-programmed death protein (PD-1) or ligand (PD-L1) and anti-cytotoxic T lymphocyte antigen (CTLA-4), have revolutionized oncology by producing dramatic shrinkage in many advanced tumor types. However, their benefits are limited by the development of unwanted autoimmune side effects (IrAEs) in up to 60% of patients. IrAEs can lead to hospitalizations, permanent organ damage, treatment interruption and even premature death. The cause of IrAEs remains poorly understood.

To study the mechanisms of IrAEs we developed a novel mouse model that recapitulates the multi-organ autoimmunity seen with immune checkpoint inhibitor treatment in patients. Using this model we can study development of IrAEs and test possible treatments to prevent these side effects in patients.

Sex Differences in Immune Responses

Immune responses differ between men and women and this sexual dimorphism impacts the prevalence and severity of many inflammatory conditions. Notably, women are more frequently affected by autoimmune disease, accounting for ~80% of cases. Mechanisms driving the female sex bias in many autoimmune diseases remain poorly understood but are important potential targets to reduce autoimmunity. Our labs studies how sex hormones and sex chromosomes modulate immune responses in autoimmune disease and cancer. Thyroid autoimmune diseases in particular show one of the strongest female sex biases (8:1 female to male) and lead to hormone dysfunction in millions of individuals.

Endocrine Autoimmune Diseases

Endocrine organs are among the most commonly affected by autoimmune disease, including the thyroid (e.g. Hashimoto’s thyroiditis, Graves’ disease) and pancreas (e.g. type 1 diabetes mellitus). Despite this, no treatments currently exist to halt autoimmune attack; instead treatment paradigms are focused on hormone replacement after gland failure. Our lab aims to change this by identifying new mechanism-based strategies to halt autoimmune endocrinopathies. We combine -omic approaches, translational studies in human specimens, and unique mouse models to identify drivers of autoimmune attack.

New Strategies to Improve Immunotherapy Outcomes in Advanced Thyroid Cancer

While most thyroid cancer is treated with surgery and radioactive iodine (RAI), and has a good prognosis, some patients have recurrent or metastatic disease affecting the neck, lungs, and bone. Few treatment options exist for RAI-refractory metastatic thyroid cancers, but advances in genetic and tumor immunology may identify new therapeutic targets.

We showed that thyroid cancers frequently lose antigen expression as a mechanism of tumor immune escape. In addition, BRAFV600E mutated tumors have increased expression of checkpoint protein PD-L1 and immune regulatory cells (Treg, MDSC). Our current work focuses on breaking thyroid cancer resistance to checkpoint immunotherapy by modulating myeloid cells in the tumor microenvironment.

Interested in participating or contributing to our research?