Human Leukocyte Antigen-G (HLA-G) Expression in Cervical Lesions: Association With Cancer Progression, HPV 16/18 Infection, and Host Immune Response

Abstract

Human leukocyte antigen-G (HLA-G) expression in 55 cervical intraepithelial neoplasia (CIN) patients with or without human papillomavirus (HPV) infection and 116 patients with squamous cell cervical cancer were examined using immunohistochemistry. Host immune response was assessed by estimating the number of intratumoral lymphocyte infiltration (TIL) in all lesions and counting CD57-expressing cells in the neoplasm lesions. The means of HLA-G immunoreactive scores were compared by the Mann-Whitney test and 1-way analysis of variance (ANOVA). The association of HLA-G expression with disease progression, HPV infection and host immune response was calculated using the Pearson Chi-square test. It was found that HLA-G expression increasingly progressed from patients with CIN 1 to CIN 2/3 and was highest in patients with cervical cancer. Human leukocyte antigen-G expression was also significantly higher in CIN and cancer patients with HPV 16/18 than in CIN patients without HPV. A significant correlation between HLA-G expression and TIL score or the counting of CD57-expressing cells was also evident in CIN patients with HPV infection and cervical cancer cases. These results suggest that HLA-G expression in cervical lesions is associated with carcinogenesis, HPV infection, and host immune response.

Human leukocyte antigen G polymorphism is associated with an increased risk of invasive cancer of the uterine cervix

“…18 Several studies have demonstrated that cervical cancer tissue expressed HLA-G and that its expression correlates with tumor progression. [5][6][7][8]10 In this report, the wildtype HLA-G*01:01:01 allele conferred protection against invasive cancer, whereas variant HLA-G*01:01:02, -G*01:06 and -G*3 0 UTR 14-bp insertion alleles increased cervical cancer risk. The HLA-G*01:01:02 and -G*01:06 alleles both have a synonymous substitution (Proline) at codon 57.…”

“…3,4 However, the link between HLA-G and cervical cancer has been inconsistent and contradictory in the published reports. For instance, HLA-G expression in cervical cancer tissue has been found to be increased, [5][6][7] reduced, 8 or absent. 9,10 HLA-G expression has correlated positively, 6,7 negatively, 5,10 or not at all 11 with cervical disease progression.…”

The paradox of IL-10-mediated modulation in cervical cancer

“…High HLA-G mRNA expression may be correlated with early carcinogenesis, since it was associated with early-stage cervical cancer (45). It was demonstrated that HLA-G expression was progressively higher in patients with CIN 1 to CIN 2/3 and was the highest in patients with cervical cancer, suggesting that HLA-G expression in cervical lesions may be associated with carcinogenesis, HPV infection and host immune response (51).…”

In Vitro Evidence of the Presence of Mesenchymal Stromal Cells in Cervical Cancer and Their Role in Protecting Cancer Cells from Cytotoxic T Cell Activity

“…For example, IL-10 can contribute by increasing HLA-G expression on HLA class Ideficient cells to escape from NK-mediated lysis through interactions with killer inhibitory receptors on NK cells [48,49]. In CeCa lesions, the expression of both HLA-G and IL-10 associated with HPV infection might play an important role in CeCa progression [50,51]. In fact, it has been recently reported that in tissue samples from biopsies derived from patients with CeCa and with loss or downregulation of HLA class I expression, most of the HLA-G-positive cases (87.5%) exhibited upregulation of the IL-10 [52].…”