Androgen Receptor Signaling Induces CD8+ T-cell Dysfunction That Is Reversed by Androgen Deprivation Therapy in Male Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) exhibits a distinct sex disparity in incidence, with a higher incidence in males than in females. Recent studies have suggested that this difference persists even after accounting for smoking and alcohol use, highlighting the need to elucidate the underlying biological mechanisms. In this study, we demonstrated that sex differences in HNSCC are androgen dependent and identified androgen receptor (AR) signaling as a key regulator of the tumor immune microenvironment by modulating CD8+ T-cell differentiation and function. Mechanically, early growth response 4 functioned as a direct downstream transcriptional effector of AR that induced CD8+ T-cell dysfunction. Clinically, androgen deprivation therapy (ADT) was an effective therapeutic strategy in HNSCC, suppressing tumor growth in mice while improving intratumoral CD8+ T-cell function. Moreover, combining ADT with immune checkpoint inhibitors led to improved antitumor efficacy. Together, these findings reveal ADT as a promising therapeutic approach to enhance the antitumor activity of sex-biased CD8+ T cells in HNSCC, which could inform the development of sex-biased immunotherapies for treating patients with HNSCC. SIGNIFICANCE: Androgen receptor engenders a sex-biased tumor microenvironment in head and neck cancer by suppressing CD8+ T-cell function, which can be overcome with androgen deprivation therapy to delay tumor progression.