Biophysical Society Conference | Tahoe 2024

Molecular Biophysics of Membranes

Thursday Speaker Abstracts

SHAPING OF CAR T CELL ACTIVATION BY THE MEMBRANE REACTION LANDSCAPE Shalini T. Low-Nam ; Kevin L Scrudders 1 ; Joy Wu 1 ; Suilan Zheng 1 ; Philip S Low 1 ; 1 Purdue, Chemistry, West Lafayette, IN, USA T cells interpret physiochemical cues within the contact zone with another cell and make fate decisions that control adaptive immune responses. For example, normal T cells detect even low densities of weak agonist ligands to activate and either relay cues to recruit other immune cells or directly kill targets. Remarkably, these global outcomes can result from the integration of signals from small numbers of binding events, collected stochastically. Recent engineering efforts have generated T cells expressing chimeric antigen receptors (CARs) that consolidate key components of T cell triggering machinery into a single transmembrane receptor capable of scanning for specific tumor antigens. There has been limited success in the application of CAR T cells in cancer immunotherapy and patients often exhibit toxicity from hyperactivation of the immune response. The mechanistic determinants for threshold setting in CAR T cells are still poorly understood. Signaling onset, at the cell surface, may be tuned by spatiotemporal, topographic, mechanical, and chemical parameters. Additionally, the local composition of the membrane itself may be consequential. We map CAR T cell inputs to cellular activation and cytotoxic responses using single molecule, single cell in vitro reconstitution assays. We find that, surprisingly, CAR T cells can mobilize cytotoxic responses to a small number of antigenic binding events, suggesting a different molecular threshold than previously appreciated. Thus, rare cells that respond to low input levels may be a source of therapeutic failures. A mechanistic understanding of CAR T cell activation setpoints and how this tuning is altered during tumor evolution will create actionable insights to optimize these therapies.

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