Mathematical Biology Seminar Jiyeon Park, University of Utah, Tueday, Febraury 25, 2025 2:00pm in LCB 215 Can cell cycle inhibitors promote immunogenicity and T cell cytotoxicity in breast cancer? Abstract: Advanced estrogen receptor positive (ER+) breast cancers are typically treated with endocrine therapy (ET) plus cell cycle inhibitors (CCI); however, nearly 20% of these cancers recur due to treatment resistance. We study the T cell based combination treatment regimen development with immune-activating cytokine, interleukin-15 (IL-15), under CCI. To understand complex interactions, we develop a nonlinear ordinary differential equation mathematical model that describes the tumor ecosystem of interacting cancer cells and cytotoxic T cells linked with pharmacokinetics of ribociclib (CCI) and IL-15, and analyze this mathematical modeling in collaboration with in vivo experiments. This dynamical model quantifies how treatments impact the promotion of T cell recruitment and T cell activation by cancer cell antigens, both in combination leading to the subsequent killing of cancer cells. Analyzing the key parameters under various dose drug combinations drives to three main findings: (1) proliferation of both cell types are suppressed by CCI, while only T cells are activated by IL-15, (2) CCI, despite slowing T cell proliferation, promote immunogenicity and immune cell toxicity in combination with IL-15, and (3) the enhanced immune capacity under this combination treatment is higher in ribociclib-resistant cancer cell lines than in sensitive cell lines. The mathematical modeling reveals that combining immune-activating treatment (IL-15) with a cell cycle inhibitor (ribociclib) outperforms single therapy in limiting cancer cell growth. Furthermore, cancer cells resistant to cell cycle inhibitors are more effectively targeted by this combination therapy.