Abstract
Abstract Regulating molecular interactions in the T cell synapse to prevent autoimmunity or, conversely, to boost anti-tumor immunity has long been a goal in immunotherapy. However, delivering therapeutically meaningful doses of immune-modulating compounds into the synapse represents a major challenge. Here, we report that covalent coupling of maleimide-functionlized nanoparticles (NPs) to free thiol groups on T cell membrane proteins enables efficient delivery of compounds into the T cell synapse. We demonstrate that surface-linked NPs are rapidly polarized toward the nascent immunological synapse (IS) at the T cell/APC contact zone during antigen recognition. To translate these findings into a novel therapeutic application we tested the NP delivery of NSC-87877, a dual inhibitor of Shp1 and Shp2, key phosphatases that downregulate T cell receptor activation in the synapse, in the context of adoptive T cell therapy of cancer. Conjugating NSC-97977-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer greatly promoted T cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. Altogether, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface.
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