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Joshua Brockman, PhDPostdoctoral Research FellowHarvard University and the Wyss Institute for Biologically Inspired Engineering
Abstract:Forces transmitted by cellular receptors regulate diverse biological processes, including hemostasis and immune function. Measuring these forces with high spatial resolution and force sensitivity remains a significant challenge. Additionally, the mechanobiology of immune cells is generally neglected in immunotherapy. New tools are needed to quantify piconewton (pN) receptor forces and to provide appropriate cues to the immune system for immunotherapy. This talk will describe the development of two mechanoimaging techniques and a T cell stimulatory biomaterial that mimics biophysical characteristics of antigen-presenting cells. The first technique, Molecular Force Microscopy, combines DNA-based molecular tension probes with fluorescence polarization microscopy to measure the 3D orientation of pN integrin forces. The second technique, tension-point accumulation for imaging in nanoscale topography (tPAINT), enables live cell super-resolution imaging of the location of receptor forces with up to 25nm spatial resolution. Importantly, multiplexed tPAINT analysis provides the ability to correlate receptor forces to the protein structures that produce them. Finally, this talk will describe an injectable biomaterial that mimics physiological T cell stimulation by presenting antigen on a fluid lipid bilayer. This material scaffold robustly stimulates T cell activation and proliferation in vitro. Additionally, subcutaneously-injected scaffolds form a local microenvironment capable of CAR-T cell restimulation in vivo and improve animal survival in an aggressive lymphoma model. Collectively, these technologies provide tools to probe cellular forces, and to use biophysical cues to improve cancer immunotherapy.
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