Effects of the Induction of Pyroptosis via Topoisomerase II Inhibition in Human Papillomavirus-Associated Vaginal and Oral Cancers on Antigen Specific Immunity

Reesman, Elizabeth
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Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide, and infection with HPV may lead to several cancers. Topoisomerase II is overexpressed in HPV-positive cancers; thus, its inhibition may differentially target cancer cells. In certain cancer cell lines, topoisomerase II inhibition was found to induce pyroptosis—a Gasdermin-mediated form of cell death characterized by pore formation in cell membranes and release of cellular contents that may function as immunostimulants and neoantigens. This study sought to determine whether topoisomerase II inhibition induces pyroptosis in HPV-positive cancers and stimulates HPV-antigen-specific immunity. TC-1 and mEER cells, two established preclinical models of HPV-positive vaginal and oral cancers, respectively, were treated in vitro with two topoisomerase II inhibitors, etoposide and mAMSA. Western blotting was used to detect markers of pyroptosis. Splenocytes from mice given HPV-oncoprotein peptide vaccines served as sources of antigen-specific T cells and were cocultured with conditioned media from topoisomerase inhibitor treatments. Flow cytometry was used to analyze immune activity. Western blotting revealed the presence of markers of pyroptosis or immunogenic cell death in both cell lines treated with topoisomerase inhibitors. Flow cytometry analysis revealed some significant relationships in treatment with topoisomerase inhibitors and antigen-specific immune activation. The findings indicate that topoisomerase II inhibition may be a promising therapeutic option for HPV-positive cancers.