Graduate student Emma Finburgh works on a Koch Institute Frontier Research Program collaboration between the Birnbaum and Ringel labs to understand how aging affects the immune system's ability to recognize and fight cancer.
Cancer is primarily a disease of aging, yet surprisingly little is known about how the aging immune system responds to tumors. Many modern cancer therapies work by harnessing the body's own T cells, but these treatments are often less effective in older patients. A Frontier collaboration between the Birnbaum and Ringel Labs is asking why.
Leading up to the Frontier award, recent work from the Ringel group showed that aging may selectively reduce the number and effectiveness of T cells that recognize certain types of tumor targets, raising the possibility that the aging process changes the repertoire of cancer-fighting T cells available to respond to developing tumors. Specifically, those early findings suggest that aging disproportionately impairs T cell responses against tumor-specific antigens, which are unique to a particular cancer, over tumor-associated antigens, which are present in both normal and cancer cells but typically more abundant in tumors.
Emma Finburgh, a lead graduate student on the Frontier team, explains that, from a technological standpoint, we are only now able to begin asking detailed questions about T cell response. “The combinatorial diversity of what T cells can recognize is very high. The tools to study this, and get at the underlying mechanisms, haven’t previously existed and are actually still being created,” she notes. Combinatorial diversity is the massive array of different molecules created by mixing and matching a basic set of blocks. In the context of T cell response, this refers to the millions of molecules T cells can recognize and respond to.
Emma is a member of the Birnbaum Lab, which develops computational and biological engineering tools to understand and manipulate T cell and other immune responses. (A recent video explains more.) She herself has spent a lot of time developing such tools, readying them for prime time. Or at least, in the case of the Frontier study, a pilot. Reflecting on how the Frontier collaboration has differed from her previous work she says, “This feels a lot more translational, to have a question to which we can begin to apply these tools, rather than focusing just on their development.”
To figure out what’s behind poorer immunotherapy response among older patients, Emma and her Frontier teammates are using mouse models of melanoma to compare anti-tumor immune responses in young and aged animals, incorporating tools and profiling approaches that link antigen specificity, T-cell receptor sequence, cell state, and function at single-cell resolution.
These studies will define how aging reshapes the T cell repertoire and identify mechanisms that contribute to impaired immune control of cancer in older individuals. Such insights could ultimately help inform therapeutic development and treatment strategies for older patients.