Redirecting engineered immune cells using G protein-coupled receptors in cancer therapy

Area of Science:

• Immunology and Cancer Therapy
• Cellular Engineering and Receptor Biology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy has transformed hematologic cancer treatment.
• CAR-T cell efficacy is limited in solid tumors due to poor immune cell migration.
• Inefficient trafficking of effector cells to the tumor site is a major hurdle.

Purpose of the Study:

• To explore engineering natural and synthetic G protein-coupled receptors (GPCRs) to enhance immune cell migration.
• To address the challenge of inefficient effector cell trafficking in solid tumor CAR T-cell therapy.
• To review strategies for improving immune cell homing, persistence, and overall efficacy.

Main Methods:

• Engineering immune effector cells to express chemokine receptors that target tumor-derived chemokines.
• Utilizing natural G protein-coupled receptors (GPCRs), specifically chemokine receptors, for enhanced chemotaxis.
• Employing synthetic GPCRs with chemogenetic and optogenetic approaches for precise cell migration control.

Main Results:

• Engineering chemokine receptors increases immune cell chemotaxis and antitumor efficacy in preclinical models.
• GPCR engineering can remodel the tumor microenvironment and alter cell metabolism.
• Synthetic GPCRs enable stimulus-controlled immune cell trafficking, overcoming limitations of natural chemokine environments.

Conclusions:

• Engineering natural and synthetic GPCRs shows significant promise for improving immune cell trafficking.
• This strategy enhances immune cell persistence and efficacy, offering a potential breakthrough for solid tumor CAR T-cell therapy.
• GPCR engineering represents a powerful tool to overcome migratory hurdles in cellular cancer therapies.