Masahito Kawazu

Allelic loss of HLA class I facilitates evasion from immune surveillance in cervical intraepithelial neoplasia

Loss of heterozygosity (LOH) has been reported to occur in HLA regions in cervical intraepithelial neoplasia (CIN) and cervical cancer. However, the details of how this is related to the progression of CIN have been unclear. In this study, we examined the human papillomavirus (HPV) antigen‐presenting capacity of people with CIN and the significance of LOH of HLA class I in the progression of CIN. It was shown that differences in antigen‐presenting capacity among each case depended on HLA types, not HPV genotypes. Focusing on the HLA type, there was a positive correlation between antigen‐presenting capacity against HPV and the frequency of allelic loss. Furthermore, the lost HLA‐B alleles had a higher HPV antigen‐presenting capacity than intact alleles. In addition, frequency of LOH of HLA class I was significantly higher in advanced CIN (CIN2–3) than in cervicitis or early‐stage CIN (CIN1): around half of CIN2–3 had LOH of any HLA class I. Moreover, the antigen‐presenting capacity against E5, which is the HPV proteins that facilitate viral escape from this immune surveillance by suppressing HLA class I expression, had the most significant impact on the LOH in HLA‐B. This study suggests that HPV evades immune surveillance mechanisms when host cells lose the capacity for antigen presentation by HLA class I molecules, resulting in long‐term infection and progression to advanced lesions.

Downregulation of HLA Class I Expression through HLA-A DNA Methylation Is Associated with Reduced CD8+ T-cell Infiltration in Cervical Cancer

Abstract Human leukocyte antigen class I (HLA-I) is central to tumor immune recognition, but its regulatory mechanisms in cervical cancer remain poorly understood. This study aimed to elucidate the impact of HLA-I regulatory mechanisms on CD8+ T-cell infiltration and identify distinct histotype-specific immune escape strategies across cervical cancer subtypes. Using 98 cervical cancer cases, including squamous cell carcinoma (SCC; n = 53), adenocarcinoma (n = 32), gastric-type adenocarcinoma (GAS; n = 5), small cell carcinoma (Small, n = 4), and mixed histologic types (n = 4), we examined the relationship between CD8+ T-cell infiltration patterns (categorized as infiltrated, excluded, or absent) and HLA-I expression, HLA-A DNA methylation, and HLA-I loss of heterozygosity (LOH). CD8+ T-cell infiltration patterns varied significantly by histologic subtype (P < 0.0001). SCC showed the highest frequency of the infiltrated pattern (73.6%), whereas GAS and Small predominantly displayed an absent pattern. Reduced CD8+ T-cell infiltration correlated with poor survival (P < 0.0001). HLA-I expression mirrored these trends being highest in SCC and lowest in Small and GAS. HLA-A DNA methylation emerged as a key driver of HLA-I downregulation, leading to reduced CD8+ infiltration (P < 0.05). In SCC, both HLA-A methylation and HLA-I LOH contributed to immune evasion; cases lacking these alterations exhibited the highest CD8+ T-cell infiltration levels (P < 0.01). This study identifies distinct HLA-I regulatory mechanisms in cervical cancer, highlighting HLA-A methylation—and particularly HLA-I LOH in SCC—as key drivers of immune evasion. These findings provide a foundation for developing predictive biomarkers and suggest that targeting these specific HLA-I regulatory mechanisms could enhance immunotherapy efficacy.