The tumor-targeted CD40 agonist CEA-CD40 promotes T cell priming via a dual mode of action by increasing antigen delivery to dendritic cells and enhancing their activation.
Details
Download: 35292514_BIB_5157B6387D0C.pdf (3136.57 [Ko])
State: Public
Version: Final published version
License: CC BY-NC 4.0
State: Public
Version: Final published version
License: CC BY-NC 4.0
Serval ID
serval:BIB_5157B6387D0C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
The tumor-targeted CD40 agonist CEA-CD40 promotes T cell priming via a dual mode of action by increasing antigen delivery to dendritic cells and enhancing their activation.
Journal
Journal for immunotherapy of cancer
ISSN
2051-1426 (Electronic)
ISSN-L
2051-1426
Publication state
Published
Issued date
03/2022
Peer-reviewed
Oui
Volume
10
Number
3
Pages
e003264
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Abstract
Tumor-targeted CD40 agonism represents an attractive strategy for cancer immunotherapy (CIT) as it promotes dendritic cell (DC) activation and concomitant tumor-specific T cell priming without causing systemic side effects. We developed the bispecific CD40 agonistic antibody CEA-CD40, which triggers CD40 stimulation exclusively in the presence of carcinoembryonic antigen (CEA), a glycoprotein specifically expressed on tumor cells. In this study, we demonstrate that CEA-CD40 can enable potent in vitro DC activation and consecutive T cell cross-priming in a CEA-specific manner. Furthermore, we provide evidence that CEA-CD40 increases colocalization of CEA <sup>+</sup> tumor material and DCs. Using CEA <sup>+</sup> tumor-derived extracellular vesicles (EVs), which are known to be an excellent tumor antigen source, we show that CEA-CD40 mediates delivery of CEA <sup>+</sup> EVs to DCs. Importantly, our data indicates that this fosters acquisition of tumor EV major histocompatibility complex I/peptide complexes by DCs, consequently improving CD8 <sup>+</sup> T cell priming against EV-associated antigen in vitro. Thus, we provide mechanistic evidence for a dual mode of action of CEA-CD40 for CIT: we suggest that CEA-CD40 has the potential to activate DCs and in addition can promote their loading with tumor antigen derived from EVs to trigger tumor-specific T cell cross-priming.
Keywords
CD40 Antigens, CD8-Positive T-Lymphocytes, Carcinoembryonic Antigen, Dendritic Cells, Humans, Neoplasms/therapy, adaptive immunity, dendritic cells, drug evaluation, preclinical, immunotherapy
Pubmed
Web of science
Open Access
Yes
Create date
21/03/2022 8:46
Last modification date
25/01/2024 7:36