CD2 augmentation enhances CAR-T-cell efficacy via immunological synapse remodeling and T-cell exhaustion mitigation

Abstract CAR-T-cell therapy has made significant strides in treating hematological malignancies, yet its efficacy is often hampered by suboptimal T-cell functionality, marked by weak antitumor capabilities and a lack of durability. The immunological synapse, a key determinant of T-cell function, is influenced by the CD58-CD2 axis. The dynamic regulation of CD2 expression on T cells impacts the quality of CAR-mediated immunological synapses, affecting CAR-T-cell functional outcomes and differentiation. Our study demonstrated that CD2 expression levels are closely linked to the quality of immunological synapses formed by CAR-T cells and their antitumor potency. Exogenous CD2 supplementation enhances the ability of CAR-T cells to form high-quality synapses, reduces T-cell exhaustion, and increases sustained antitumor efficacy. Additionally, ectopic CD2 expression increases CAR-T-cell sensitivity to low-density antigens. Thus, replenishing CD2 in CAR-T cells is a promising strategy to increase the therapeutic efficacy of CAR-T-cell therapy.