Speaker
Description
T cell exhaustion is a dysfunctional state that develops after prolonged antigen exposure, in which T cells progressively lose effector function. Exhaustion is marked by the sustained expression of inhibitory receptors which transmit suppressive signals that limit immune activity. Recent studies indicate that the 24 hour period after initial antigen exposure is a critical window in the determination of T cell fate. Monoclonal therapeutic antibodies that target inhibitory receptors boost immune function by disrupting suppressive signaling pathways and have been shown to aid in the recovery of cytotoxic function. In this project, we explore trajectories of early phase T cell exhaustion and the impact of immune checkpoint intervention within the first 24 hours of antigen exposure by constructing a multiscale, off-lattice 3D model of the tumor microenvironment. We couple an agent-based model of cell–cell interactions with a reaction–diffusion model for antibody transport and track exhausting interactions between cancer and effector T cells. We assess parameter sensitivity by computing first-order and total-order Sobol indices. We highlight key factors that influence T cell migration and progression into an exhaustive state. Our analysis provides insights into how microenvironmental and therapeutic parameters influence T cell function and may inform future modeling strategies for immunotherapy optimization.
