Crosstalk Between Immunity and Oncogenes Within the Tumor Microenvironment of HPV-Associated Cervical Squamous Cell Carcinoma

Reham M Alahmadi,1 Halah Z Al Rawi,2 Maaweya Awadalla,2 Bashayer Saeed,2 Basma Abdelazeem,2 Huda M Alshanbari,3 Bandar Alosaimi2 1Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia; 2Research Center, King Fahad Medical City, Riyadh Second Health Cluster, Riyadh, Saudi Arabia; 3Department of Mathematical Sciences, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi ArabiaCorrespondence: Bandar Alosaimi, Email [email protected]: Every two minutes, a woman dies from cervical cancer, which is considered the fourth most common cancer among women worldwide. The dynamic interplay between tumor inflammation, immune crosstalk, oncogenes, and tumor suppressor genes plays a crucial role in tumor development and progression.Methods: Using clinical and integrated bioinformatics, the mRNA expression pattern of 168 immune and tumor-related genes in the tumor microenvironment (TME) of HPV-positive cervical squamous cell carcinoma (CSCC) was analyzed.Results: The study identified 94 DEGs, of which 55 genes were remarkably upregulated, including CASP8, ZHX2, BCL2L1, CTNNB1, RB1, BAX, CD274, CCL20, FOXP3, and CCL18. The top three-fold changes were associated with CASP8, ZHX2, and BCL2L1, respectively. In contrast, downregulation was discovered for 39 genes associated with immunity, regulation of cell cycle, and DNA damage response (HRAS, CCND1, ATM, CXCR1, and MIF). Gene-gene interaction and correlation analysis showed positive correlations, including RB1 and CASP8, RB1 and BCL2L1, and CCL20 with CCL18. Notably, six genes exhibited increased expression and showed a strong correlation with enhanced overall survival (OS) and disease-free survival (DFS), indicating their potential utility as prognostic biomarkers. Upregulated genes were positively associated with various immune cells, including B cells, CD8+ and CD4+ T cells, macrophages, neutrophils, and dendritic cells. Functional enrichment analysis revealed involvement in cancer-related processes, inflammatory responses, and cell migration, with key pathways linked to cytokine signaling and chemokine receptor interactions.Discussion: Through the integration of clinical, experimental, and computational analyses, potential therapeutic targets and prognostic biomarkers were identified that may help improve clinical outcomes. Future studies should focus on the functional assays of identified genes both in vitro and in vivo.Plain Language Summary: This study examined a subtype of cervical cancer associated with HPV infection. We analyzed the activity of 168 cancer- and immune-related genes in tumor samples and identified 94 genes with abnormal expression 55 were upregulated and 39 were downregulated. Several upregulated genes were associated with improved patient survival and increased immune cell presence. These findings suggest that certain genes could serve as useful indicators for prognosis and treatment strategies. Keywords: tumor microenvironment, TME, human papillomavirus, HPV, cervical squamous cell carcinoma, CSCC