pTα 增强 mRNA 翻译并提升 CAR-T 细胞清除实体瘤的能力

Current chimeric antigen receptor (CAR) therapies are effective against a range of hematological malignancies and autoimmune disorders but have shown limited activity against solid tumors. In searching for effective means to enhance the functional persistence and potency of CAR T cells, we explored the potential of integrating pre-T cell features into canonical CD28-based CARs. Thymocytes undergo a proliferation burst during the -selection developmental stage, which is driven by the pre-T cell receptor and its unique pT chain.

CARs harboring the pT 1A domain imparted greater expansion, cytokine production, and in vivo persistence to T cells, accompanied by lowered exhaustion and greater long-term tumor control in multiple liquid and solid tumor models. CARs incorporating the 1A domain showed sustained phosphorylation of the mRNA translation master regulator Y-Box Binding Protein 1 (YBX1), which was required for enhanced tumor eradication. The programming of mRNA translation in T cells opens another avenue for regulating and potentiating immunotherapy.