CXCL13 Expression Promotes CAR T Cell Antitumor Activity and Potentiates Response to PD-1 Blockade

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cell therapies are effective cancer treatments.
• Solid tumors present challenges due to immunosuppressive microenvironments and T cell exhaustion, limiting therapy efficacy.

Purpose of the Study:

• To investigate the role of CXCL13 in enhancing CAR T cell function and response to ICB.
• To evaluate the therapeutic potential of CXCL13-overexpressing CAR T cells in solid tumors.

Main Methods:

• Bioinformatic analysis identified elevated CXCL13 in ICB responders.
• Engineered mouse and human CAR T cells to overexpress CXCL13.
• Assessed T cell phenotype, mitochondrial function, proliferation, and in vivo antitumor activity, including combination with PD-1 inhibition.

Main Results:

• CXCL13 overexpression reduced T cell exhaustion and increased central memory phenotype, mitochondrial function, and proliferation.
• CXCL13-engineered CAR T cells demonstrated enhanced in vivo antitumor activity.
• Combination therapy with PD-1 inhibition further improved CAR T cell expansion and persistence, particularly in early exhausted CD8+ T cells.
• CXCL13 conferred similar benefits to human CAR T cells in vitro.

Conclusions:

• CXCL13 expression improves CAR T cell function and responsiveness to immune checkpoint blockade.
• CXCL13 is a promising strategy for optimizing CAR T cell therapy in solid tumors.
• This approach holds translational relevance for clinical applications.