肿瘤内在对 IFN-γ 促凋亡效应的敏感性是 CD4⁺ CAR-T 细胞抗肿瘤活性的主要决定因素

CD4 + T cells and CD4 + chimeric antigen receptor (CAR) T cells display highly variable antitumor activity in preclinical models and in patients; however, the mechanisms dictating how and when CD4 + T cells promote tumor regression are incompletely understood. With the help of functional intravital imaging, we report that interferon (IFN)- production but not perforin-mediated cytotoxicity was the dominant mechanism for tumor elimination by anti-CD19 CD4 + CAR T cells.

Mechanistically, mouse or human CD4 + CAR T-cell-derived IFN- diffused extensively to act on tumor cells at distance selectively killing tumors sensitive to cytokine-induced apoptosis, including antigen-negative variants. In anti-CD19 CAR T-cell-treated patients exhibiting elevated CAR CD4:CD8 ratios, strong induction of serum IFN- was associated with increased survival.

We propose that the sensitivity of tumor cells to the pro-apoptotic activity of IFN- is a major determinant of CD4 + CAR T-cell efficacy and may be considered to guide the use of CD4 + T cells during immunotherapy.