4-1BB 与 DAP10 联合促进 NKG2D(bbz) CAR-T 细胞增殖与持久性

Chimeric antigen receptor (CAR)-T cell therapy has been shown to have considerable therapeutic effects in hematological malignancies, and NKG2D(z) CAR-T cell therapy has been verified to be safe based on clinical trials.

However, due to the poor persistence of NKG2D(z) CAR-T cells, their therapeutic effect is not obvious.

Here, we constructed NKG2D(bbz) CAR-T cells that can simultaneously activate 4-1BB and DAP10 costimulatory signaling. They were found to be cytotoxic to the target cells in vitro and in vivo . They exhibited low differentiation, low exhaustion, and good proliferation.

Importantly, the proportions of central memory T (Tcm) and stem cell-like memory T (Tscm) cell subsets were strikingly increased. After long-term incubation with the target cells, they displayed reduced exhaustion compared to NKG2D(z) CAR-T cells.

Further, in the presence of the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, they exhibited reduced exhaustion and apoptosis, upregulated Bcl2 expression, and an increased proportion of Tcm cell subsets.

Finally, NKG2D(bbz) CAR-T cells had better antitumor effects in vivo . In summary, the results showed that NKG2D(bbz) CAR-T cells may be valuable for cellular immunotherapy of cancer.