Correlation between subsets of tumor-infiltrating immune cells and risk stratification in patients with cervical cancer
Authors: Chen Rui , Gong Yi , Zou Dongling , Wang Lifeng , Yuan Li , Zhou Qi 
Published: October 2019

Aim
To investigate the correlation between clinicopathological features and risk stratification in cervical cancer patients, and evaluate the feasibility of tumor-infiltrating immune cells as prognostic biomarkers in clinical practice.

Methods
CD3+ tumor infiltrating T cells (TILs), CD45RO+ TILs, CD4+ TILs, CD8+ TILs, FOXP3+ TILs (regulatory T cells, Tregs), CD68+ tumor associated macrophages (TAMs), CD163+ TAMs, and PD-L1+ tumor cells were immunostained in formalin-fixed paraffin-embedded (PPFE) tissues from 96 cervical cancer patients. Immunostaining density and other clinicopathological features such as age, FIGO stage, histopathologic type, Ki67 index, HPV status, lymhovasular invasion status (LVI), lymph node metastasis, tumor size, stromal invasion status, surgical margin status, and parametrial invasion, were evaluated for their roles in risk stratification of cervical cancer patients.

Results
The results showed that significant differences of lymph node metastasis (p = 0.003), surgical margin status (p = 0.020), and stromal invasion status (p = 0.004) existed between lVI(−) and LVI(+) patients. CD3+ TILs in the central tumor area (p = 0.010), CD4+ TILs in the central tumor area (p = 0.045), CD8 + TILs in the central tumor area (p = 0.033), and CD8+ TILs in the invasive margin area (p = 0.004) showed significant differences between lVI(−) and LVI(+) patients. When patients were grouped by status of lymph node metastasis, significant differences of FIGO stage (p = 0.005), LVI status (p = 0.003), CD3+ TILs in the central tumor area (p = 0.045), CD45RO+ TILs in the central tumor area (p = 0.033), and CD45RO+ TILs in the invasive margin area (p = 0.028) were also observed. After the patients were stratified into low-, intermediate-, and high risk groups, significant differences of FIGO stage (p = 0.018), status of lymph node metastasis (p = 0.000), LVI status (p = 0.000), parametrial invasion status (p=0.012), stromal invasion status (p = 0.000), tumor growth pattern (p = 0.015) and tumor size (p = 0.000) were identified among 3 groups of patients, while only CD45RO+ TILs in the invasive margin area (p = 0.018) and FOXP3+ TILs in the central tumor area (p = 0.009) were statistically different among three groups of patients. Spearman’s correlation analysis demonstrated that FIGO stage, LVI status, status of lymph node metastasis, parametrial invasion, stromal invasion status, and tumor size positively correlated with risk stratification (P = 0.005, 0.020, 0.000, 0.022, 0.000, and 0.000 respectively), while CD45RO+ TILs in the invasive margin area and FOXP3+ TILs in the central tumor area showed statistically negative correlation with risk stratification (P = 0.031, 0.009 respectively).

Conclusion
Our study suggested that CD45RO+ TILs in the invasive margin area and FOXP3+ TILs in the central tumor area might be useful biomarkers for risk stratification in cervical cancer patients. Large cohort studies of cervical cancer patients are required to validate our hypothesis.