Our Research and Focus
It is becoming increasingly clear that host-based immunosuppressive factors inhibit the immune response from eliminating cancer and chronic viral infections. Many of the same factors suppress the immune responses against multiple chronic diseases, suggesting conserved underlying mechanisms mediate immune dysfunction. As a result, it may be possible to simultaneously develop strategies that target central drivers of immunosuppression to fight multiple diseases. Our lab has been the first to discover many new mechanisms of immune regulation and our discoveries are being tested to treat and predict outcomes of human disease. To understand the immune mechanisms that promote control of cancer and chronic infections, our laboratory uses multiple cutting-edge high dimensional approaches to interrogate mouse models, human tissues, and clinical trials. This is found in our four research areas.
Type I interferons (IFN-Is) during viral persistence, cancer, and therapy
Type I interferons (IFN-Is) are central inflammatory regulators of anti-tumor immunity and responses to immunotherapy. However, IFNs also drive feedback inhibition through expression of multiple suppressive factors that enable tumor growth and underlie therapy resistance. A major focus of our group is to:
-
Understand how IFNs generate these opposing signals
-
Understand how these signals are communicated to drive immune exhaustion
-
Discover where they occur spatially within the tissue
-
Discover how to therapeutically modulate IFN-I signaling to uncouple the positive and negative aspects of IFN-I signaling to enhance immune restorative therapies.
Mechanisms of T cell exhaustion
Underlying the inability to control cancers and chronic viral infections is the attenuation of CD8 T cell function (termed exhaustion). As a result, the ability to restore function to these exhausted T cells is critical for the outcome of multiple therapeutic modalities, including checkpoint blockade and adoptive T cell / CAR T cell transfer. Our group is interested in:
-
Defining the underlying mechanisms that promote and sustain T cell exhaustion during chronic infections and tumors
-
Apply this understanding to the goal of restoring their function to eliminate these diseases.
CD4 T cell help and differentiation in infection and cancer
CD4 T cells are central to orchestrating the immune response and their presence is critical to sustain ongoing immune responses in chronic infections, and likely cancer. Yet, the cellular and molecular changes that comprise CD4 T cell functional alterations in these diseases are poorly understood. Adding to this complexity is the multiple T helper (Th) differentiation states that CD4 T cells progress toward, making it necessary to consider functional and molecular changes within the context of specific Th differentiation states. Our goal is to: understand:
-
Understand how CD4 T cells differentiate
-
Understand how CD4 T cells are maintained during chronic disease
-
Define the molecular basis of CD4 T cell help in these chronic diseases
-
Define the cellular interactions and spatial organization wherein “help” is delivered
-
Determine how CD4 T cells respond to immune restorative therapies
-
Identify ways to therapeutically utilize CD4 T cells to eliminate infections and cancer.
Human cancer and clinical trial analysis
We are integrally involved with the Princess Margaret Tumor Immunotherapy Program (TIP) and their Immune Profiling Team. Our group is involved in the analysis of clinical trial samples and through our fantastic collaborators, we have access to human samples from multiple tumor types for analysis. We are involved in probing these samples to:
-
Identify biomarkers associated with therapy
-
Immune characterization within the tumor microenvironment
-
Understand the basic biology studies of the function and spatial organization of immune: cancer interactions.