title: Synapse-directed delivery of immunomodulators using T-cell-conjugated nanoparticles.
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 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-87877-loaded NPs to the surface of tumor-specific T cells just prior to adoptive transfer into mice with advanced prostate cancer promoted a much greater T-cell expansion at the tumor site, relative to co-infusing the same drug dose systemically, leading to enhanced survival of treated animals. In summary, our studies support the application of T-cell-linked synthetic NPs as efficient drug delivery vehicles into the IS, as well as the broad applicability of this new paradigm for therapeutically modulating signaling events at the T-cell/APC interface.
authors.affiliation: Department of Material Science and Engineering, Massachusetts Institute of Technology-MIT, Cambridge, MA 02139, USA.
authors.forename: Matthias T
authors.initials: MT
authors.lastname: Stephan
authors.forename: Sirkka B
authors.initials: SB
authors.lastname: Stephan
authors.forename: Peter
authors.initials: P
authors.lastname: Bak
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000627:therapeutic use; D054992:Immunological Synapses / Q000378:metabolism*; D007167:Immunotherapy; D008297:Male; D008301:Maleimides / Q000737:chemistry; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000737:chemistry*; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000628:therapy; D013438:Sulfhydryl Compounds / Q000737:chemistry; D013601:T-Lymphocytes / Q000166:cytology*
chemical_list: D007155:Immunologic Factors; D008301:Maleimides; D013438:Sulfhydryl Compounds; C043592:maleimide