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

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...

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Bibliographic Details
Published in:Journal for immunotherapy of cancer 2022-03, Vol.10 (3), p.e003264
Main Authors: Sum, Eva, Rapp, Moritz, Dürr, Harald, Mazumdar, Alekhya, Romero, Pedro J, Trumpfheller, Christine, Umaña, Pablo
Format: Article
Language:English
Subjects:
adaptive immunity
Antigens
Cancer
Carcinoembryonic Antigen
CD40 Antigens
CD8-Positive T-Lymphocytes
Clinical/Translational Cancer Immunotherapy
Dendritic Cells
drug evaluation, preclinical
Extracellular vesicles
Humans
Immunotherapy
Lymphocytes
Neoplasms - therapy
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Summary: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+ tumor material and DCs. Using CEA+ tumor-derived extracellular vesicles (EVs), which are known to be an excellent tumor antigen source, we show that CEA-CD40 mediates delivery of CEA+ 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+ 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.
ISSN:2051-1426
2051-1426
DOI:10.1136/jitc-2021-003264