A fusion protein that targets antigen-loaded extracellular vesicles to B cells enhances antigen-specific T cell expansion.
Academic Article
Overview
abstract
Extracellular vesicles (EVs) have the potential to modulate immune responses via their cargo molecules and are being explored as vehicles in cancer immunotherapy. Dendritic cell-derived EVs can induce antigen-specific immune responses leading to reduced tumor burden. This response was shown to depend partially on B cells. EVs can be targeted to certain cells or tissues, and EVs from Epstein-Barr Virus (EBV) infected cells were shown to carry the EBV glycoprotein GP350 on their surface and target human CD21 (hCD21) on B cells. We therefore investigated whether targeting EVs to B cells via this mechanism could improve antigen-specific immune responses. A soluble fusion protein containing the phosphatidylserine-binding domain (C1C2) of lactadherin and hCD21-binding domain (D123) of GP350 was used to decorate and target EVs to B cells. D123-decorated EVs increased in vitro B cell targeting 5-fold compared to EVs decorated with a non-targeting control protein or undecorated EVs. Furthermore, in vivo, D123-decoration did not alter the biodistribution of EVs across organs but specifically targeted them to B cells in the spleen, blood and lymph nodes of hCD21-transgenic mice. Immunization with hCD21-targeted, OVA-loaded EVs resulted in a higher percentage of antigen-specific CD8+ T cells compared to untargeted EVs. Our data show that D123-decorated EVs efficiently target B cells and improve antigen-specific T cell responses in vivo, which could be explored in future therapeutic applications.
