Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity

Bousso and colleagues show that IFN-gamma production is the dominant tumor elimination mechanism exerted by CD4(+) CAR T cells and define tumor cell sensitivity to IFN-gamma as a determinant of CD4(+) CAR T efficacy. 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)-gamma 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-gamma 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-gamma was associated with increased survival. We propose that the sensitivity of tumor cells to the pro-apoptotic activity of IFN-gamma is a major determinant of CD4(+) CAR T-cell efficacy and may be considered to guide the use of CD4(+) T cells during immunotherapy.