Enhanced Radiation Sensitivity in HPV-Positive Head and Neck Cancer

TLDR

HPV‑positive head and neck cancers have markedly better survival than HPV‑negative tumors, yet published data on this difference remain inconsistent. The study aims to evaluate whether the superior survival of HPV‑positive HNC justifies de‑escalating radiation and chemotherapy in clinical trials. Researchers performed systematic in‑vitro and in‑vivo assays on validated HPV‑positive and HPV‑negative HNC cell lines, complemented by genome‑wide microarray analysis of gene expression 24 h after radiation. HPV‑positive HNCs exhibited markedly higher intrinsic radiosensitivity (SF2 0.22 vs 0.59), prolonged G2‑M arrest, increased apoptosis, and upregulation of TP53‑related genes, while TP53 knockdown induced resistance, confirming that functional p53 mediates the enhanced radiation response.

Abstract

Patients with human papillomavirus (HPV+)-associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV-negative (HPV-) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV- HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV-: 0.59 vs. HPV+: 0.22; P < 0.0001), corresponding with a prolonged G2-M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV- cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV- HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome.