Negative immune factors might predominate local tumor immune status and promote carcinogenesis in cervical carcinoma

Minyi Zhao,Qian Zhang,Yang Li,Shimin Quan,Xiaofeng Yang,Meili Pei,Ting Yang,Li Wang,Yang Yu,Di Cao,Juan Zhao,Sijuan Tian,Xing Wei,Yanping Guo,Hongran Jia

doi:10.1186/s12985-016-0670-8

Minyi Zhao, Qian Zhang + Show 13 more

Open Access

https://doi.org/10.1186/s12985-016-0670-8

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Abstract

BackgroundThe disequilibrium of local immune microenvironment is an essential element during tumorigenesis.MethodBy conducting real-time polymerase chain reaction, we identified the mRNA level of immune factors, FoxP3 (forkhead box protein P3), CCL22/CCR4 (chemokine (C-C motif) ligand 22/CC chemokine receptor 4), OX40L/OX40 (tumor necrosis factor superfamily member 4/tumor necrosis factor receptor superfamily member 4) and Smad3 (SMAD family member 3) in neoplastic foci and its periphery tissues from 30 cases of squamous cervical carcinoma and 20 cases of normal cervix.ResultThe FoxP3, CCL22 and CCR4 mRNA level in local immune microenvironment of normal cervix was lower than that in cervical cancer. While OX40L, OX40 and Smad3 mRNA level profile in normal cervix was higher than that in cervical cancer. Beyond individual effect, the pairwise positive correlations were demonstrated among the mRNA level of FoxP3, CCL22 and CCR4. The mRNA level of OX40 negatively correlated with CCL22, but positively correlated with Smad3. Moreover, the mRNA level of FoxP3 and CCL22 was increased while Smad3 was decreased in cervical tissue with HPV (human papilloma virus) infection.ConclusionOur data yields insight into the roles of these immune factors in cervical carcinogenesis. It may therefore be that, in microenvironment of cervical squamous cell carcinoma, along with the context of HPV infection, negative immune regulators FoxP3, CCL22 and CCR4 might overwhelm positive immune factors OX40L, OX40 and Smad3, giving rise to an immunosuppressive status and promote the progression of cervical carcinogenesis.Trial registrationNot applicable.

Highlights

The disequilibrium of local immune microenvironment is an essential element during tumorigenesis
To ascertain Forkhead box protein P3 (FoxP3), Chemokine ligand 22 (CCL22) and CC chemokine receptor 4 (CCR4) mRNA level in cervical carcinoma, we quantified their expression in 30 cases of neoplastic foci with adjacent tissue and 20 healthy control
The results exhibited the mRNA level of FoxP3, CCL22 and CCR4 of local microenvironment in cervical cancer was significantly higher than that in normal cervix

Summary

Introduction

The disequilibrium of local immune microenvironment is an essential element during tumorigenesis. FoxP3 + Treg has been identified as a notorious immunosuppressive cell in local site. The CCL22CCR4 axis could induce the expression of FoxP3 in Tregs [11] and infiltrate FoxP3 + Treg selectively into tumor sites, contributing to form an immunocompromised environment in favor of tumor growth. OX40 is highly expressed on effector T cells and Tregs. Its ligand named OX40L, is mostly localized on activated APC (antigen presenting cell). Plenty of evidences have demonstrated that OX40L-OX40 axis is of great importance to impede the suppressive function of Treg by inhibiting TGF-β-driven (transforming growth factor-β) conversion of naive CD4+ FOXP3− T cells into CD4+FOXP3+ T cells [12]. TNF-α (tumor necrosis factor-α) impairs the differentiation and function of TGF-β-induced FoxP3 + Tregs by inhibiting the phosphorylation of Smad. Low expression of Smad has been found in acute T-cell lymphoblastic leukemia [14] and gastric carcinoma [15]

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