Microsatellite instability analysis in tumors with different mechanisms for total loss of HLA expression

Down-regulation of the expression of major histocompatibility complex molecules is a frequent event that is associated with the poor immunogenicity of tumor cells. Acquired resistence to T-cell-based immunotherapy has been associated with loss of functional beta(2)-microglobulin expression. This anomaly appears to be particularly relevant in tumors exhibiting a defect in DNA-mismatch repair, and induces structural abnormalities in HLA cell-surface expression that are not reversible by cytokine treatment. We examined HLA expression in 118 melanoma, colon or larynx tumors to identify total loss of HLA class I expression with or without somatic beta 2-microglobulin gene mutation. Microsatellite instability was investigated in these tumors to determine whether a replication error phenotype (RER+) implied a particular alteration in HLA phenotype. A total of 7.6% of the tumors showed the RER+ phenotype, and 12.7% were HLA-ABC-negative. In the RER+ group, only one tumor was HLA-ABC-negative and no beta 2-microglobulin mutation was identified. In contrast, in the HLA-ABC-negative group, only one tumor showed microsatellite instability. None of the three melanomas that contained beta 2-microglobulin mutation exhibited the mutator phenotype. These findings suggest that beta 2-microglobulin mutation in human melanoma tumors may arise through a mechanism that does not necessarily involve microsatellite instability. Our results also indicate that somatic mutations of the beta 2-microglobulin gene are not the main mechanism of total loss of HLA expression.