Dissertation Proposal Defense: Diego Chowell Puente
Diego Chowell Puente, an applied mathematics for the life and social sciences graduate student in the School of Human Evolution and Social Change, will defend his dissertation proposal, "Mathematical and Computational Models of Cancer and the Immune System."
The immune system plays a dual role during cancer progression. It can suppress tumor growth by eliminating cancer cells, and promote neoplastic expansion by either selecting for tumor cells that are fitter to survive in an immunocompetent host or by establishing the right conditions within the tumor microenvironment. First, we present a model to study the dynamics of clonal evolution of cancer. We model selection through time as an epistatic process. That is, the fitness change in a given cell is not simply additive, but depends on previous mutations. Our simulation studies indicate that tumors are composed of myriads of small subclones at the time of diagnosis. Because some of these rare subclones harbor pre-existing treatment-resistant mutations, they present a major challenge to precision medicine.
Second, we address the question of self and non-self discrimination by the immune system. By performing a quantitative analysis of the biochemical properties of thousands of MHC class I peptides, we find that hydrophobicity of T cell receptors contact residues is a hallmark of immunogenic epitopes. Based on these findings, we further develop a computational model to predict immunogenic epitopes which facilitate the development of T cell vaccines against pathogen and tumor antigens. Last, we study the evolutionary and immunological basis for clinical response to immune checkpoint blockade therapy. For this purpose, we analyze melanoma genomic data from clinical responders and non-responders to CTLA-4 blockade. We find extensive neoepitope depletion in tumors of a subset of non-responders. This suggests that these tumors have undergone “immunoediting,” thus impacting clinical response to CTLA-4 blockade therapy.
The defense is open to the public.