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Objective:We investigated the correlations between cyclin-dependent kinase 4/6 (CDK4/6) levels and human papillomavirus (HPV) infection state in head and neck squamous cell cancer (HNSCC).The aim was to explore the potential value of CDK4/6 inhibitors in the treatment of HNSCC.Methods:Multiomic sequencing data for HNSCC were obtained from The Cancer Genome Atlas (TCGA),and the mRNA levels and copy number variations (CNVs) of CDK4 and CDK6 were strictly analyzed.Overall survival (OS) curves were produced using the Kaplan-Meier method,and survival differences between groups were assessed by the log-rank test.Next,gene set enrichment analysis (GSEA) was applied to interrogate CDK4/6-associated molecular pathways in HPV-positive (HPV+) and HPV-negative (HPV-) HNSCC.Last,lymphoid cell infiltrates in each type of HNSCC were explored,and the correlations between CDK4/6 expression and lymphoid infiltrates were explored by Tumor Immune Estimation Resource (TIMER) analysis.Results:Overexpression of either CDK6 or CDK4 was not a relevant factor for OS in HPV-HNSCC (CDK6:top 40％ vs.bottom 40％,P=0.885;CDK4:top 40％ vs.bottom 40％,P=0.267).In HPV+ HNSCC,CDK6 but not CDK4 was a relevant factor for OS (CDK6:top 40％ vs.bottom 40％,P=0.002;CDK4:top 40％ vs.bottom 40％,P=0.452).GSEA found that overexpressed CDK6 in HPV+ HNSCC inhibited pathways involved in the tumor immune response,suggesting its roles in antitumor immunity.TIMER analysis results revealed that CDK6 but not CDK4 accumulation was negatively correlated with the number of tumor-infiltrating lymphocytes specific for HPV+ HNSCC,which led to tumor response suppression.Conclusions:CDK6,but not CDK4,is a poor prognostic marker specific in HPV+ HNSCC patients.Overexpressed CDK6 might stimulate tumor progression by suppressing lymphocytes infiltration independent of its kinase activity.Only abrogating its kinase activity using current CDK4/6 inhibitors was not enough to block its tumor promotion function.