research
T cell cancers are extreme outliers of T cell function. My work has focused on the genetics of these cancers, harnessing mutations for T cell engineering and to gain new insights in immunology.
Genomic studies of human outliers reveal new biology and therapeutics.
Drugs where the target is associated with human genetic evidence are more likely to succeed in the clinic than those without. For example, studying outliers of human cholesterol levels has revealed key pathways and led to successful therapies (e.g. PCSK9 inhibitors).
Outliers of T cell function include immunodeficiencies at one end, while autoimmunity and T cell cancers represent the other.
Repurposing T cell cancer mutations enhances T cell therapies.
T cell therapies face numerous barriers to success, including limited persistence and the harsh tumor microenvironment.
Sourcing solutions to these problems from T cell cancers differs from prior approaches in three important ways:
- 01 Mutation variety. Gene fusions, gain-of-function point mutations, and gain-of-function truncations are all sampled by cancer.
- 02 Antigen dependence. These mutations often rely on antigenic stimulation to exert their effects, which contributes to safety.
- 03 Evolved in humans. They have already evolved and been validated in humans in vivo.
By screening T cell lymphoma mutations, a fusion gene CARD11-PIK3R3 emerged as the top hit. In syngeneic mouse models, it dramatically enhances anti-tumor efficacy over 100 fold, highlighting the utility of studying human outliers to develop novel T cell therapies. Nature 2024
The genetics of T cell cancers uncovers T cell biology.
The phenotype of cancer arises from a combination of mutations and cell of origin. Studying T cell cancers has yielded insights into T cell signaling as well as revealed novel cell types that the cancers arise from.
PD-1 mutations are a negative prognostic indicator in T cell lymphomas of the skin through control of T cell signaling, metabolism, and epigenetics. This has implications for PD-1 function in normal T cells and targeted therapies for T cell lymphoma patients.Blood 2021Nature Cancer 2023
Cell of origin, as identified by distinct T cell receptor expression, explains clinical differences in skin gamma delta T cell lymphomas, and reflects the layers of the skin different gamma delta cells typically occupy. Nature Communications 2020
What I'm excited about going forward:
I predict there will be much more to learn from cancer mutations.
Are there other useful mutations we can harness to solve new problems or enhance other cell types?
What are the mechanisms by which different mutations reprogram T cell biology?
Can we apply mutations uncovered in humans to synthetic biology, and develop new solutions to various engineering problems?