Tetsuo Ushiku

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.