Tumor-Associated CD163+ M2 Macrophage Infiltration is Highly Associated with PD-L1 Expression in Cervical Cancer

Fan Guo,1,2,* Yang-chun Feng,1,2,* Gang Zhao,3 Ran Zhang,4 Zhen-zhen Cheng,1 Wei-na Kong,1,2 Hui-li Wu,1 Bin Xu,1 Xiang Lv,1 Xiu-min Ma1,2 1State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi 830011, People’s Republic of China; 2The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, People’s Republic of China; 3Department of Blood Transfusion, Affiliated Traditional Chinese Medicine Hospital of Xinjiang Medical University, Urumqi 830000, People’s Republic of China; 4Clinical Pathology Center, Tumor Hospital Affiliated to Xinjiang Medical University, Urumqi 830000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiu-min MaState Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Clinical Laboratory Center, Tumor Hospital Affiliated to Xinjiang Medical University, No. 789 Suzhou Road, Urumqi 830011, People’s Republic of ChinaEmail maxiumin1210@sohu.comBackground: Programmed death-ligand 1 (PD-L1) is a negative costimulatory molecule, and its main function is widely considered to be in the regulation of T cells. Tumor-associated macrophages (TAMs) are an important part of the tumor microenvironment, and they also play an important role in immunosuppression. However, the relationship between the expression of PD-L1 and TAMs in cervical carcinoma (CC) remains unclear. We detected the expression of PD-L1 and TAMs in tumor tissue to study the correlation between them.Methods: Immunohistochemical staining of PD-L1, CD68 (pan-macrophage), and CD163 (M2-like macrophage) was performed in 120 cases of cervical squamous cell carcinoma. Logistic regression analysis was used to evaluate the predictors related to positive PD-L1 expression. We also apply the Kaplan–Meier method to study the recurrence-free and overall survival rate of CC patients.Results: The increase in PD-L1 expression in tumor cells (TC) was significantly correlated with the increase in CD163 density (r=0.8550, p< 0.0001), while PD-L1 in the stroma was also significantly associated with the intratumoral density of CD68- or CD163-positive cells (CD68 p< 0.0001; CD163 p=0.0009). The mean infiltration rates of CD68- and CD163-positive cells in PD-L1-positive TC were significantly higher than in PD-L1-negative TC (CD68 p=0.0095; CD163 p< 0.0001). In multivariate logistic regression analyses, only the density of CD163-positive cells was correlated with the expression of PD-L1 in TC cells (OR 1.52; p=0.032). In prognostic analysis, PD-L1 more than 10% was significantly correlated with short RFS (HR=2.66; p=0.028). For CD163+ macrophage evaluation, the density above the median was also significantly correlated with RFS (HR=2.48; p=0.021).Conclusion: CD163+ M2-like macrophage infiltration is highly associated with PD-L1 expression in CC, suggesting that macrophage infiltration can serve as a potential therapeutic target.Keywords: cervical cancer, programmed death-ligand 1, macrophages, tumor microenvironment