Ganglioside-Functionalized Nanoparticles for Chimeric Antigen Receptor T-Cell Activation at the Immunological Synapse
Year: 2022
Type: article
Abstract: Chimeric Antigen Receptor (CAR) T cell therapy has proven to be an effective strategy against hematological malignancies but persistence and activity against solid tumors must be further improved. One emerging strategy for enhancing efficacy is based on directing CAR T cells to antigen presenting cells (APCs). Activation of CAR T cells at the immunological synapse (IS) formed between APC and T cell is thought to promote strong, persistent antigen-specific T cell-mediated immune responses but requires integration of CAR ligands into the APC/T-cell interface. Here, we demonstrate that CAR ligand functionalized, lipid-coated, biodegradable polymer nanoparticles (NPs) that contain the ganglioside GM3 (GM3-NPs) bind to CD169 (Siglec-1)-expressing APCs and localize to the cell contact site between APCs and CAR T cells upon initiation of cell conjugates. The CD169 + APC/CAR T-cell interface is characterized by a strong optical colocalization of GM3-NPs and CARs, enrichment of F-actin, and recruitment of ZAP-70, indicative of integration of GM3-NPs into a functional IS. Ligands associated with GM3-NPs localized to the APC/T-cell contact site remain accessible to CARs and result in robust T-cell activation. Overall, this work identifies GM3-NPs as a potential antigen delivery platform for active targeting of CD169 expressing APCs and enhancement of CAR T-cell activation at the NP-containing IS.
Source: ACS Nano
Authors: Han Zang, Menna Siddiqui, Suryaram Gummuluru, Wilson W. Wong, Björn M. Reinhard
Institution: Boston University
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Illuminating Dynamic Receptor Clustering in the Epidermal Growth Factor Receptor Signal Transduction Pathway Using Plasmon Coupling, Plasmonic Inactivation of Virus and Mycoplasma Contaminants, GM3 Nanoparticles for Sustained Delivery of Anti-Retrovirals to Lymphatic Tissues, Signals that establish and maintain HIV latency, Advanced laser scanning confocal microscope for multiple users, PLACENTAL PROTEIN 14 AS A UNIQUE IMMUNOREGULATOR, Precise targeting of T1D specific T cells using CAR and peptide-MHC chimeric antigen ligands, Precise tumor targeting with logic CAR circuits
OpenAlex ID: W4307234997