Evaluation of CD4⁺ cells infiltration as a prognostic factor in cervical intraepithelial neoplasia 2

Objective: To identify candidate predictors for the prognosis of cervical intraepithelial neoplasia 2 (CIN2) lesions and evaluate the prognostic value of the local immune response. Methods: One hundred fifteen CIN2 patients were enrolled. The percentage of p16-, minichromosome maintenance complex component 2-or apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G)-positive cells was determined immunohistochemically. Tumor-infiltrating lymphocytes (TILs) in intertumoral lesions were scored using an automated system. CIN3 disease progression and regression rates were estimated by the Kaplan–Meier method. A case-control study was conducted to screen CIN2 prognostic factors in 10 regression and 10 progression patients. Selected factors were examined in a cohort study to determine their prognostic value for CIN2. Results: Among all participants, the cumulative progression and regression rates at 60 months were 0.477 and 0.510, respectively. In the case-control study, p16-and APOBEC3G-positive cells were higher in the progression group (p=0.043, p=0.023). Additionally, CD4⁺ cell infiltration was enhanced in the regression group (p=0.023). The cohort study revealed a significantly increased progression rate in patients with elevated p16-positive cells (p<0.001), and increased CD4⁺ TIL infiltration was associated with better regression (p=0.011). Kaplan– Meier analysis according to human papillomavirus (HPV) positivity revealed a greater CIN3 development risk in HPV16-positive patients than in HPV16-negative cases. Finally, multivariate analysis identified HPV16 infection and CD4⁺ TIL infiltration as independent prognostic factors in CIN2 regression. Conclusion: CD4⁺ TIL infiltration in intertumoral lesions was related with CIN2 regression. Our findings suggest CD4⁺ TIL infiltration may be useful for the triage of CIN2 patients.