Abstract C002: Reverse Transcriptase Inhibition Enhances Demethylation-Induced Immune Activation and tumor cell toxicity in HPV+ OPSCC

Abstract Human papillomavirus (HPV) causes ∼80% of oropharyngeal squamous cell carcinoma (OPSCC) and its incidence continues to rapidly increase in the U.S. When compared to head and neck cancers that are associated with tobacco, HPV16+ OPSCCs respond better to therapy and have higher cure rates. This cure, however, comes at a great cost to patients since most HPV+ OPSCCs are treated with aggressive therapy that includes high dose fractionated radiation and concurrent cisplatin. Moreover, despite relatively good cure rates for HPV+ OPSCC patients, 20-30% will develop recurrences with few treatments available. While the approval of immune checkpoint inhibitors (ICI) for head and neck cancer has a great promise to improve outcomes, novel strategies to maximize neoadjuvant response to ICI in HPV+ OPSCC are needed to decrease postoperative therapy and associated morbidity. Previously, we found that global demethylation causes tumor cell toxicity and immune activation in HPV+ OPSCC that is driven by increased expression of Long Interspersed Element-1 (Line1) and Line1 retrotransposition. Blocking retrotransposition with reverse transcriptase inhibitor lamivudine elevated demethylation-induced interferon signaling and DNA damage in leading to enhanced toxicity in HPV+ head and neck cancer cells. Moreover, treating HPV+ PDXs with demethylating agent 5-aza and lamivudine significantly inhibited tumor growth in mice. We suggest that combination od 5-aza and reverse transcriptase inhibitors could act as a powerful primer to increase treatment response of HPV+ OPSCC to ICIs. Citation Format: Sri Vemulamanda, Hina Rehmani, Lewis Russel, Xue Li, Wendell Yarbrough, Natalia Issaeva. Reverse Transcriptase Inhibition Enhances Demethylation-Induced Immune Activation and tumor cell toxicity in HPV+ OPSCC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C002.