Microwave treatment of human papillomavirus-positive in vitro grown epithelial tissues results in a rapid stress-related transcriptional response and induction of innate immunity

Background Hyperthermia is a well-documented adjunct to cancer therapy. Recently, it has begun to gain traction in the treatment of human papillomavirus (HPV)-driven pathologies. Microwaves offer a precise and targeted approach to deliver hyperthermia and are already in use in the clinic for the treatment of plantar and common warts: non-oncogenic HPV-driven cutaneous lesions.Purpose To determine if microwave-delivered hyperthermia may be applicable for the treatment of oncogenic HPV-positive anogenital mucosal lesions and to better understand the molecular mechanisms underlying microwave-delivered hyperthermia.Methods Three-dimensional in vitro grown HPV16-infected epithelial tissues were subject to hyperthermia using microwave treatment. RNA sequencing was used to examine changes to the transcriptome following microwave treatment.Results Microwave treatment rapidly altered the transcriptome, with 59 genes differentially expressed at 4 h post-treatment. Of these genes, three were downregulated and 56 upregulated. At later time points post-treatment, 150 genes were differentially expressed, and all of these were upregulated. Microwave treatment triggered a heat shock response, with many chaperones and co-chaperones upregulated, which are important in preventing proteolysis following temperature rises. Significant upregulation of many of these genes has previously been reported in transcriptomic studies that used other methods of delivering hyperthermia. Microwave hyperthermia increased expression of genes involved in immune pathways, including interleukins (IL8, IL20, IL24), interferons (IFNĸ) and chemokines (CCL24, CCL26).Conclusions The data have important implications for the recurrence of HPV-driven pathology following microwave treatment.