Out of the bitter came forth sweet: Activating CD28-dependent co-stimulation via PD-1 ligands

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Programmed cell death 1 (PD-1) is a key negative regulator of T-cell responses.
• Dysregulation of PD-1 signaling contributes to chronic inflammation, viral infections, and cancer.
• Current strategies aim to modulate T-cell activity for therapeutic benefit.

Purpose of the Study:

• To develop a novel chimeric co-stimulatory molecule to enhance T-cell effector functions.
• To investigate the potential of diverting inhibitory PD-1 signals into activating signals.
• To assess the therapeutic efficacy of the engineered molecule in preclinical cancer models.

Main Methods:

• Construction of a fusion protein (PD-1/28) combining the extracellular domain of PD-1 with the intracellular domain of CD28.
• Transduction of human T cells to express the PD-1/28 chimeric molecule.
• Evaluation of T-cell activation, proliferation, cytokine secretion, and anti-tumor activity in xenograft models.

Main Results:

• Engineered T cells expressing PD-1/28 showed increased cytokine secretion and upregulated activation markers.
• PD-1/28 expression enhanced T-cell proliferative potential compared to control T cells.
• Transduced T cells demonstrated superior anti-neoplastic activity against human melanoma xenografts.

Conclusions:

• The novel PD-1/28 chimeric molecule effectively converts inhibitory PD-1 signals into co-stimulatory signals.
• This approach represents a promising strategy for enhancing T-cell-mediated anti-tumor immunity.
• PD-1/28 fusion protein holds potential for therapeutic applications in cancer and other immune-related diseases.