Correlation of Circulating CD64+/CD163+ Monocyte Ratio and stroma/peri-tumoral CD163+ Monocyte Density with Human Papillomavirus Infected Cervical Lesion Severity

Abstract

HPV infected cervical cells secrete mediators that are gradually changed and have influence on infiltrating M2 phenotypic monocytes in cervical lesions. However, profiles of circulating immune cells in women with cervical lesions and M2 phenotypic monocyte activity in HPV infected cervical lesions are limited. This study aimed to investigate circulating monocyte populations correlated with M2 phenotype density and its activity in HPV infected cervical lesions. HPV DNA was investigated in cervical tissues using PCR. High risk HPV E6/E7 mRNA was detected using in situ hybridization. CD163 immunohistochemical staining was performed for M2 macrophage. CD163 and Arg1 mRNA expression were detected using real-time PCR. Circulating monocyte subpopulations were analyzed using flow cytometry. CD163 and Arg1 mRNA expression were increased according to cervical lesion severity and corresponding with density of M2 macrophage in HSIL and SCC in stroma and peri-tumoral areas. Additionally, the relationship between M2 macrophage infiltration and high risk HPV E6/E7 mRNA expression was found and corresponded with cervical lesion severity. Circulating CD14CD16 and CD14CD163 monocytes were elevated in No-SIL and cervical lesions. Interestingly, CD14CD64 monocyte was greatly elevated in HSIL and SCC, whereas intracellular IL-10 monocytes were not significantly different between cervical lesions. The correlation between increasing ratio of circulating CD64/CD163 monocyte and density of infiltrating CD163 monocytes was associated with severity of HPV infected cervical lesions. The elevated circulating CD64/CD163 monocyte ratio correlates to severity of HPV infected cervical lesions and might be a prognostic marker in cervical cancer progression.

The role of the innate and adaptive immune response in HPV‐associated oropharyngeal squamous cell carcinoma

“…These effects result in promotion of carcinogenesis and metastasis. Although not specific to HPV‐associated OPSCC, TAMs are linked to poor prognosis, progression of disease, locoregional metastasis, and higher grade lesions . The M1 phenotype, however, is associated with tumor regression and inducing HPV clearance by favoring a TH1 response .…”

Activities of stromal and immune cells in HPV-related cancers

“…It was reported that poor prognosis is linked to increased levels of CD163 (TAM marker with M2 phenotype), CSF-1 (colony-stimulating factor-1), major regulator of macrophage lineage, and Arginase-1 (Arg-1) – markers of TAM’s activity – in several cancers including the HPV-related ones [ 12 , 25 , 28 ]. Increased infiltration of CD163 macrophages in stromal and peri-tumoral areas were associated with malignancy progression, lymph node metastasis, higher FIGO stages [ 29 ], higher lesion grades and cervical cancer specimens [ 28 , 30 ].…”

<p>Cervical Cancer: Emerging Immune Landscape and Treatment</p>

“…More importantly, higher FIGO stage and lymph node metastasis or lymphangiogenesis usually showed larger counts of M2 macrophages. 70 – 72 M2 macrophages are usually associated with poor prognosis. CC cell lines possibly induce more monocytes toward an M2-like phenotype in TAMs, significantly maintaining a tumor immunosuppressive microenvironment and promoting angiogenesis and metastasis.…”