Transcriptomic profiling of peripheral blood cells in HPV‐associated carcinoma patients receiving combined valproic acid and avelumab

Abstract

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.