IFN-γ 抵抗型 CD28 CAR-T 细胞在多种小鼠肿瘤模型中显示生存、疗效与持久性提升

Interferon- (IFN- ) plays complex and, sometimes, contradictory roles in cancer, which can affect patient responses to treatments such as immunotherapies.

We recently demonstrated that IFN- production by chimeric antigen receptor (CAR) T cells is not required for efficacy in hematologic tumor models, whereas IFN- receptor (IFN- R) signaling in solid tumor cells facilitates CAR T cell adhesion and antigen-specific cytotoxicity.

Here, we show that IFN- induces apoptosis of CAR T cells bearing a CD28 intracellular signaling domain, which can be reduced through targeting of IFN- or IFN- R. In hematologic malignancies, knockout of IFN- R (IFN- RKO) in CAR T cells increased their persistence without compromising efficacy. In xenograft and syngeneic solid tumor models, IFN- R knockout CAR T cells displayed more potent tumor control, prolonged survival, and improved T cell memory that conferred protection from tumor rechallenge.

RNA sequencing of tumor-infiltrating IFN- RKO CAR T cells derived from tumor-bearing mice revealed increased cell death in tumor cells. Collectively, these data show that inhibition of IFN- signaling can increase the expansion and antitumor activity of CD28-based CAR T cells in liquid and solid tumors.