Abstract 3183: Adrenergic signaling augments cytotoxic T-cell anti-tumor function in p53-deficient head and neck cancer

Abstract Few advances have been made against head and neck cancers, in part because treatment efforts have focused on the epithelial component of these tumors. However, therapies targeting the microenvironment, including immune checkpoint blockade (ICB), also remain ineffective in the majority of head and neck cancers. Like some other immunotherapy-nonresponsive tumors, head and neck cancers develop a complex microenvironment heavily infiltrated by nerve fibers arising from the peripheral nervous system. Studies in multiple models have shown that the ablation of different portions of the peripheral nervous system prevents cancer development and progression. We recently showed that existing nerves sprout and undergo autonomic reprogramming to an adrenergic-like phenotype as a result of orchestrated microRNA (miRNA) shuttling from cancer cells to neurons, resulting in activation of transcriptional programs that establish new neuronal identity. Given that activated T-cell subsets express high levels of adrenergic receptors, we hypothesized that adrenergic signaling may also influence tumor-infiltrating T-cell function. We used novel murine models of OCSCC to discern the effect of adrenergic nerve signaling on immune infiltration and immunotherapy response and correlated our findings with data from patient cohorts using bulk and single-cell RNA sequencing. We found that adrenergic signaling acutely enhanced cytotoxic T-cell activity in patient-derived tumor/T-cell pairs, and we elucidated a p53-dependent mechanism underlying this effect. Ultimately, these results provide a striking contrast to the known role of adrenergic signaling in cancer development: although nerve-cancer crosstalk drives cancer aggression and progression, tumor innervation may also better enable the host immune response. Therapeutic approaches targeting this critical component of tumor biology may be useful to improve patients' survival, treatment responses, and quality of life. Citation Format: Deborah Silverman, Sara Leahey, Shamima Akhter, Tongxin Xie, Yunfei Wang, Elien Doordjuin, George Calin, Jeffrey Myers, Patrick Hwu. Adrenergic signaling augments cytotoxic T-cell anti-tumor function in p53-deficient head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3183.