Redirected primary T cells harboring a chimeric receptor require costimulation for their antigen-specific activation

Area of Science:

• Immunology
• Cancer Biology
• Molecular Engineering

Background:

• Chimeric receptors (CRs) show promise for tumor cell eradication.
• Existing CR approaches are limited in targeting cancer cells lacking costimulatory receptor ligands.
• A novel antibody-based tripartite chimeric receptor (TPCR) was engineered to overcome these limitations.

Purpose of the Study:

• To evaluate the efficacy of a novel tripartite chimeric receptor (TPCR) in activating primary T cells.
• To assess the TPCR's ability to target cancer cells lacking specific surface ligands.
• To determine the potential of TPCR for clinical immunotherapy applications.

Main Methods:

• Generated a TPCR construct containing scFv, CD28 signaling domain, and FcRgamma subunit.
• Utilized CR-transgenic (Tg) mice expressing the TPCR or a truncated version (Tg-TPCRDeltaCD28).
• Stimulated T cells with hapten-modified target cells and TNP-protein coated surfaces.

Main Results:

• TPCR-expressing T cells, but not CD28-truncated controls, activated upon stimulation with hapten-modified target cells lacking B7.
• TPCR-Tg T cells exhibited full activation, including proliferation, IL-2 production, apoptosis resistance, and target cell killing.
• TPCR-Tg mice demonstrated delayed-type hypersensitivity response without prior priming.

Conclusions:

• The tripartite chimeric receptor (TPCR) effectively drives primary T cell activation.
• TPCR enables T cell responses against target cells lacking costimulatory ligands.
• TPCR represents a promising receptor configuration for clinical immunotherapy using T or stem cells.