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Modular delivery of co-stimulatory signals through a PD-1-based immunoswitch receptor improves the functionality of Hepatitis B Virus-specific engineered T cells.
Front. Immunol. 17, DOI: 10.3389/fimmu.2026.1821414 (2026)
In chronic hepatitis B virus infection (cHBV), T-cell responses are
skewed. This prevents the elimination of HBV-infected hepatocytes,
contributes to hepatocellular carcinoma development, and limits the
efficacy of T-cell therapies. To counteract the immune checkpoint
PD-1/PD-L1–interaction in adoptive T-cell therapy, we developed
PD-1–based immunoswitch receptors that convert PD-L1 engagement into
co-stimulation. We designed immunoswitch receptors linking a PD-1
ectodomain to intracellular CD28, 4-1BB, or OX40 signaling domains and
expressed them in HBV-specific chimeric antigen receptor (CAR)- and
T-cell receptor-engineered T cells. T-cell activity was assessed in
antigen- and PD-L1-dependent co-cultures, transcription factor reporter
systems, and an HBV carrier mouse model. Second-generation S-CAR
functionality was not improved by signal stacking of additional
co-stimulatory domains, resulting in a dysfunctional activation state
rather than an additive benefit. In contrast, modular delivery of
co-stimulation through PD-1-based immunoswitch receptors enhanced
antigen sensitivity, functionality, and cytotoxicity of engineered T
cells. PD-L1 supplied in trans was sufficient to support on-target
functionality of engineered T cells by immunoswitch receptor
co-stimulation. PD-1_4-1BB proved superior at inducing sustained NF-κB
signaling and reducing exhaustion-associated pathways. In vivo,
PD-1_4-1BB improved T-cell persistence and decreased TOX upregulation.
PD-1–based immunoswitch receptors offer a modular strategy to strengthen
engineered T-cell responses against HBV antigen-expressing cells in the
liver’s tolerizing environment. This ligand-driven approach enables
precise tuning of co-stimulation, generating a versatile platform for
enhancing adoptive T-cell therapies in chronic infections and cancer.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Chimeric Antigen Receptor ; Receptor ; Ectodomain ; Adoptive Cell Transfer ; Cytotoxic T Cell ; Hepatitis B Virus ; Antigen ; Immune Receptor
ISSN (print) / ISBN
1664-3224
e-ISSN
1664-3224
Zeitschrift
Frontiers in Immunology
Quellenangaben
Band: 17
Verlag
Frontiers
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Virology (VIRO)