Disruption of TOX transcription factors enhances CAR T cells function in solid tumors

Abstract T cells expressing chimeric antigen receptors (CARs) have shown impressive therapeutic efficacy against leukemias and lymphomas, but have not been as effective against solid tumors because chronic stimulation with tumor antigens causes them to enter a hyporesponsive (“exhausted” or “dysfunctional”) state. Here we show that the high-mobility group (HMG)-box transcription factors TOX and TOX2 are highly expressed in CAR-expressing exhausted (PD-1highTim3high) CD8+ tumor-infiltrating lymphocytes (TILs). CAR TILs deficient in both TOX and TOX2 (TOX DKO) suppressed tumor growth and prolonged survival of tumor-bearing mice, compared to wildtype (WT), TOX-deficient or TOX2-deficient CAR TILs; they also showed increased effector function with increased TCF1 expression and decreased expression of the inhibitory receptors PD-1, LAG3 and CD160. Like NR4A transcription factors, TOX and TOX2 are critical for the transcriptional program of hyporesponsiveness downstream of NFAT. Disruption of TOX expression or activity could be a promising strategy for cancer immunotherapy.