Human leukocyte antigen II (HLA-II) plays an important role in host immune responses to
cancer cells. Changes in gene methylation may result in aberrant expression of HLA-II, serving a key role in the pathogenesis of Kazakh
esophageal squamous cell carcinoma (ESCC). We analyzed the expression level of HLA-II (
HLA-DP, -DQ, and -DR) by immunohistochemistry, as well as the methylation status of
HLA-DRB1 and
HLA-DQB1 by MassARRAY spectrometry in Xinjiang Kazakh ESCC. Expression of HLA-II in ESCC was significantly higher than that in
cancer adjacent normal (
ACN) samples (P < 0.05). Decreased HLA-II expression was closely associated with later clinical stages of ESCC (P < 0.05). Hypomethylation of
HLA-DRB1 and hypermethylation of
HLA-DQB1 was significantly correlated with occurrence of Kazakh ESCC (P < 0.01), and mainly manifested as hypomethylation of CpG9, CpG10-11, and CpG16 in
HLA-DRB1 and hypermethylation of CpG6-7 and CpG16-17 in
HLA-DQB1 (P < 0.01). Moreover, hypomethylation of
HLA-DQB1 CpG6-7 correlated with poor differentiation in ESCCs, whereas hypermethylation of
HLA-DRB1 CpG16 and hypomethylation of
HLA-DQB1 CpG16-17 were significantly associated with later stages of ESCC (P < 0.05). A significant inverse association between
HLA-DRB1 CpG9 methylation and HLA-II expression was found in ESCC (P < 0.05). These findings suggest aberrant
HLA-DRB1 and
HLA-DQB1 methylation contributes to the aberrant expression of HLA-II. These molecular changes may influence the immune response to specific
tumor epitopes, promoting the occurrence and progression of Kazakh ESCC.