TLR9 Agonists Potentiate Adoptive T Cell Therapy in Cancer through a B Cell-CD2 Costimulatory Axis

Area of Science:

• Immunology
• Cancer Biology
• Cell Therapy

Background:

• Adoptive T cell transfer (ACT) shows promise for cancer treatment.
• Toll-like receptor (TLR) agonists can enhance ACT efficacy.
• Understanding TLR agonist mechanisms is key to optimizing ACT.

Purpose of the Study:

• To elucidate the mechanism by which TLR agonists enhance ACT.
• To identify specific pathways and molecules involved in TLR-mediated ACT potentiation.
• To explore the role of B cells and CD2 costimulation in ACT response.

Main Methods:

• Investigated TLR9-activated B cells and their effect on CD8+ T cells in murine and human systems.
• Utilized various TLR agonists, focusing on class B CpG.
• Disrupted CD2 signaling and assessed its impact on T cell function and tumor control.
• Performed gain-of-function experiments with CD2 stimulation on tumor-infiltrating lymphocytes and CAR T cells.
• Correlated CD2 expression in human tumors with patient survival data.

Main Results:

• TLR9-activated B cells enhance CD8+ T cell fitness and antitumor activity via CD2 costimulation.
• Class B CpG uniquely programmed T cells for superior effector function, metabolism, and tumor control.
• Disrupting CD2 signaling impaired T cell glycolytic capacity and reduced tumor control.
• CD2 stimulation mimicked TLR9 agonism effects on T cell effector function.
• Elevated CD2 expression in human tumors correlated with improved patient survival.

Conclusions:

• A novel innate-adaptive circuit involving TLR9-activated B cells and CD2 costimulation potentiates ACT.
• Class B CpG and CD2 signaling represent a targetable pathway to enhance cell therapy for solid tumors.
• CD2 costimulation is a critical factor in improving T cell-based cancer immunotherapy.