Abstract
The progression of human papillomavirus (HPV) infection in the anogenital tract has been associated with the involvement of cells with regulatory properties. Evidence has shown that glucocorticoid-induced tumor necrosis factor receptor (GITR) is an important surface molecule for the characterization of these cells and proposes that GITR ligand may constitute a rational treatment for many cancer types. We aimed to detect the presence of GITR and CD25 in cervical stroma cells with and without pathological changes or HPV infection to better understand the immune response in the infected tissue microenvironment. We subjected 49 paraffin-embedded cervical tissue samples to HPV DNA detection and histopathological analysis, and subsequently immunohistochemistry to detect GITR and CD25 in lymphocytes. We observed that 76.9% of all samples with high GITR expression were HPV-positive regardless of histopathological findings. High GITR expression (77.8%) was predominant in samples with ≥ 1,000 RLU/PCB. Of the HPV-positive samples negative for intraepithelial lesion and malignancy, 62.5% had high GITR expression. High GITR expression was observed in both carcinoma and high-grade squamous intraepithelial lesion (HSIL) samples (p = 0.16). CD25 was present in great quantities in all samples. The predominance of high GITR expression in samples with high viral load that were classified as HSIL and carcinoma suggests that GITR+ cells can exhibit regulatory properties and may contribute to the progression of HPV-induced cervical neoplasia, emphasizing the importance of GITR as a potential target for immune therapy of cervical cancer and as a disease evolution biomarker.
Highlights
The progression of human papillomavirus (HPV) infection in the anogenital tract has been associated with the involvement of cells with regulatory properties
Studies show that Treg cells are activated with greater sensitivity than naïve effector T cells after antigenic stimulation, which has been attributed mainly to their semi-activated state that is thought to be due to the increased expression of CD25 (α-chain of the IL-2 receptor), glucocorticoid-induced tumor necrosis factor receptor (GITR) markers, and others[9,10,11]
Given the findings that indicate the involvement of cells with regulatory properties, especially Treg cells, in the progression of cervical malignant lesions[3,4,23,24], this study aimed to detect both CD25 and GITR markers in lymphocytes of cervical stroma to better understand the immune response in the microenvironment of HPV infection, which may shed light on novel therapeutic interventions against intraepithelial neoplasia and cervical cancer of viral etiology, and perhaps make GITR a possible candidate biomarker for disease evolution
Summary
The progression of human papillomavirus (HPV) infection in the anogenital tract has been associated with the involvement of cells with regulatory properties. High GITR expression was observed in both carcinoma and high-grade squamous intraepithelial lesion (HSIL) samples (p = 0.16). Conclusions: The predominance of high GITR expression in samples with high viral load that were classified as HSIL and carcinoma suggests that GITR+ cells can exhibit regulatory properties and may contribute to the progression of HPV-induced cervical neoplasia, emphasizing the importance of GITR as a potential target for immune therapy of cervical cancer and as a disease evolution biomarker. Human papillomavirus (HPV) infects the basal and parabasal cells of squamous epithelium in the female anogenital tract, and HPV types 16, 18, 31, 33, and 45 in particular are believed to put patients at high risk for the development of high-grade cervical intraepithelial neoplasia (CIN) and cervical carcinoma[1]. Studies show that Treg cells are activated with greater sensitivity than naïve effector T cells after antigenic stimulation, which has been attributed mainly to their semi-activated state that is thought to be due to the increased expression of CD25 (α-chain of the IL-2 receptor), glucocorticoid-induced tumor necrosis factor receptor (GITR) markers, and others[9,10,11]
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