Clinical Significance of Tumor Infiltrating T-Helper and Regulatory Cells in Bulgarian Cervical Cancer Patients

<b>Background and Objectives:</b> Cervical cancer (CC), primarily caused by human papillomavirus (HPV) infection, is the most common gynecological cancer and a leading cause of cancer-related death in women. The immune microenvironment, particularly CD4+ T-helper cells and FOXP3 (forkhead box P3)+ regulatory T cells (Tregs), plays a crucial role in tumor progression. However, the exact relationship between immune cell infiltration and clinical outcomes in CC is not fully understood. This study aimed to examine the association between CD4+ T-helper cells, FOXP3+ Tregs, and clinical/pathological parameters in CC patients. Methods: We conducted a retrospective analysis of 150 patients with T1-stage cervical cancers diagnosed between 2015 and 2021. Tumor samples were evaluated using immunohistochemistry (IHC) to assess CD4+ and FOXP3+ TILs in intratumoral and stromal regions. Additionally, deconvoluted transcriptomic data from the TCGA cohort were used to assess immune infiltration within the tumor immune microenvironment (TIME). <b>Results:</b> High infiltration of CD4+ T-helper cells was significantly associated with better overall survival (OS) in node-negative CC patients (<i>p</i> = 0.0006). However, no significant prognostic value was found for Tregs. CD4+ cells were more prevalent in patients with well-differentiated tumors (G1 and G2) and lower levels of CD4+ infiltration were found in squamous cell carcinoma (SCC) compared to other histological subtypes. Multivariate regression analysis showed that only tumor size (T1b3) and undifferentiated tumor morphology (G3) were significantly associated with poorer OS. In contrast, infiltration of CD4+ or FOXP3+ cells did not significantly correlate with OS after adjusting for clinical factors. Competing risk analysis for death from cancer showed no significant associations with immune cell infiltration levels. <b>Conclusions:</b> This study underscores the complex relationship between immune cell infiltration and clinical outcomes in CC. While CD4+ T-helper cell infiltration is associated with improved prognosis in node-negative cases, further research is necessary to clarify the role of Tregs and other immune components in the tumor microenvironment. These findings suggest potential avenues for therapeutic strategies, including immune checkpoint inhibitors, in CC.