Journal
MOLECULAR ONCOLOGY
Volume -, Issue -, Pages -Publisher
WILEY
DOI: 10.1002/1878-0261.13519
Keywords
IL-18; IL-8; immunotherapy; prognostic biomarker; RNA sequencing
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Human papillomavirus (HPV)-associated cancer can evade the immune system by creating a suppressive tumor microenvironment. This study suggests that combining the epigenetic agent valproic acid (VA) with avelumab, an immunotherapy drug, may enhance antitumor immunity in HPV-associated solid tumors. Measuring plasma IL-8/IL-18 levels and performing bulk RNA-Seq on PBMCs could serve as valuable biomarkers to predict immunotherapy outcomes.
Human papillomavirus (HPV)-associated cancer continues to evade the immune system by promoting a suppressive tumor microenvironment. Therefore, immunotherapy appears to be a promising approach for targeting HPV-associated tumors. We hypothesized that valproic acid (VA) as an epigenetic agent combined with avelumab may enhance the antitumor immunity in HPV-associated solid tumors. We performed bulk RNA-sequencing (RNA-Seq) on total peripheral blood mononuclear cells (PBMCs) of seven nonresponders (NRs) and four responders (Rs). A total of 39 samples (e.g., pretreatment, post-VA, postavelumab, and endpoint) were analyzed. Also, we quantified plasma analytes and performed flow cytometry. We observed a differential pattern in immune response following treatment with VA and/or avelumab in NRs vs. Rs. A significant upregulation of transcripts associated with NETosis [the formation of neutrophil extracellular traps (NETs)] and neutrophil degranulation pathways was linked to the presence of a myeloid-derived suppressor cell signature in NRs. We noted the elevation of IL-8/IL-18 cytokines and a distinct transcriptome signature at the baseline and endpoint in NRs. By using the receiver operator characteristics, we identified a cutoff value for the plasma IL-8/IL-18 to discriminate NRs from Rs. We found differential therapeutic effects for VA and avelumab in NRs vs. Rs. Thus, our results imply that measuring the plasma IL-8/IL-18 and bulk RNA-Seq of PBMCs may serve as valuable biomarkers to predict immunotherapy outcomes.
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