The transcription factor Helios restrains the anti-tumor capacity of CD8+ T cells

Immunotherapy has revolutionized cancer treatment, but it lacks efficacy in a sizable fraction of patients. Therefore, understanding the transcriptional networks that limit CD8+ T cell anti-tumor responses is fundamental. Here, we show that Helios, a transcription factor that maintains suppressive function in CD4+ regulatory T cells, is induced in tumor-infiltrating CD8+ T cells in human and murine cancer. Genetic deletion of Helios in CD8+ T cells reduced tumor growth, decreased the number of intra-tumoral terminally exhausted CD8+ T cells, and increased the frequency of cells with a transcriptional profile indicative of progenitor capacity. The combination of Helios and PD-1 deficiencies robustly improved the antitumoral capacity of CD8+ T cells. A small molecule screen identified a drug able to inhibit Helios expression and its administration improved the anti-tumoral effect of PD-1 deficiency. These results demonstrate that Helios represents a therapeutic target that could boost anti-cancer immunotherapy.