The transcription factor IRF4 determines the anti-tumor immunity of CD8+ T cells

Abstract

Understanding the factors that regulate Tcell infiltration and functional states in solid tumors is crucial for advancing cancer immunotherapies. Here, we discovered that the expression of interferon regulatory factor 4 (IRF4) was a critical Tcell intrinsic requirement for effective anti-tumor immunity. Mice with T-cell-specific ablation of IRF4 showed significantly reduced Tcell tumor infiltration and function, resulting in accelerated growth of subcutaneous syngeneic tumors and allowing the growth of allogeneic tumors. Additionally, engineered overexpression of IRF4 in anti-tumor CD8+ Tcells that were adoptively transferred significantly promoted their tumor infiltration and transition from a naive/memory-like cell state into effector Tcell states. As a result, IRF4-engineered anti-tumor Tcells exhibited significantly improved anti-tumor efficacy, and inhibited tumor growth either alone or in combination with PD-L1 blockade. These findings identify IRF4 as a crucial cell-intrinsic driver of Tcell infiltration and function in tumors, emphasizing the potential of IRF4-engineering as an immunotherapeutic approach.