Supplementing CD2 expression enhances CAR-T Cell Efficacy through Optimizing CAR-immunological Synapse formation

CAR-T cell therapy has made significant strides in treating hematological malignancies, yet its efficacy is often hampered by T cells' suboptimal functionality, marked by weak antitumor capabilities and 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 synapses, affecting CAR-T cells' functional outcomes and differentiation. Our study confirmed 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 CAR-T cells' ability to form high-quality synapses, reduces T cell exhaustion, and boosts sustained antitumor efficacy. Additionally, ectopic CD2 expression increases CAR-T cells' sensitivity to low-density antigens. Thus, replenishing CD2 in CAR-T cells is a promising strategy to enhance the therapeutic efficacy of CAR-T cell therapy. Gene expression profile analysis of RNA-seq data from CAR-T cells and CD2-CAR T cells after multiple rounds of antigen stimulation. Samples were collected before antigen stimulation, after 1 round of antigen stimulation, and after 3 rounds of antigen stimulation. The CAR-T cells and CD2-CAR T cells were derived from three donors.