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

Toll-like receptor (TLR) agonists improve the efficacy of ACT therapy, but the underlying mechanism of potency remains poorly understood. Here, we identify a previously unrecognized innate-adaptive circuit in which TLR9-activated B cells augment CD8 T cell fitness and antitumor activity through CD2-dependent costimulation.

Among multiple TLR agonist tested, class B CpG uniquely programmed murine and human CD8⁺ T cells for superior effector differentiation, metabolic fitness and antitumor control. Disruption of CD2 signaling blunts the benefits of TLR9 agonism, including glycolytic capacity and tumor control. Independently, blocking CD86/CD80/CD28 or ICOS did not impair CpG conditioned CD8 T cell anti-tumor activity.