Understanding the genetic factors associated with treatment response in HPV-related head and neck cancer.
Jenna Bouassaly, Nader Sadeghi, Michael Hier, Alex Mlynarek, Marco Mascarella, Alan Spatz, Derin Calgar, Kalil Sultanem, Willian Foulkes, Moulay Alaoui-Jamali, Severine Landais, Olivier Gingras, Sabrina Daniela da Silva
Recently, there has been an increase in the incidence of head and neck cancer (HNC), particularly of human papillomavirus (HPV)-related oropharyngeal cancer (OPC). Despite superior patient prognoses, the standard of care for HPV-positive OPC remains surgery followed by radiotherapy or chemoradiotherapy, which often result in severe long-term side effects like facial disfiguration, dysphagia, xerostomia, and pain. Our group has a novel de-escalated strategy for HPV-positive OPC that utilizes neoadjuvant chemotherapy (NCT) followed by transoral robotic surgery, which was shown to be highly effective in a clinical trial (ClinicalTrials.gov - NCT04277858). As some patients still exhibited partial responses (pPR), we aim to determine possible causes of treatment resistance. Preliminary enriched pathway analyses of RNAseq and miRNAseq data revealed differences in gene expression and tumor immune microenvironment (TME) signatures in pPR tumors, leading us to hypothesize that these factors may be involved in treatment resistance and could be targeted to enhance response. Single-cell spatial genomic analyses were performed to characterize the differences in TME and identify specific differentially expressed gene (DEG) targets in pPR tumors. Potential DEG targets were identified from spatial data, and differences in pre- and post-treatment immune cell composition are expected between NCT responders and nonresponders. Planned analyses include CRISPR modulation of select DEGs in OPC cell lines to elucidate their role in treatment response, and immune co-culture of the modified cells to assess the implications of the DEGs on the TME. Understanding the genetic mechanisms of treatment resistance in HPV-OPC can open the door to alternative treatments for patients with resistant tumors.