HLA-DR signaling inhibits Fas-mediated apoptosis in A375 melanoma cells.

Although melanocytes are devoid of the human major histocompatibility complex class II (HLA II) molecules, melanomas often display constitutive expression of these molecules, particularly HLA-DR. This constitutive expression of HLA-DR molecules is associated with tumor progression and poor prognosis but the molecular basis for this association remains poorly understood. Within the hypothesis of a role in immune escape, we analyzed the regulation of Fas-mediated apoptosis by HLA-DR signaling in the HLA-DR-positive malignant melanoma cell line A375. Our study demonstrates that engagement of HLA-DR molecules with anti-HLA-DR-specific monoclonal antibody L243 significantly reduces Fas-mediated apoptosis; DNA fragmentation and cell death were decreased by 50% and 40%, respectively. We found that while HLA-DR signaling does not affect Fas receptor expression, it significantly reduces Fas-induced activation of caspase-8 and Bid. Furthermore, inhibition studies and expression of dominant negative form of Mek-1 demonstrated that HLA-DR-mediated inhibition of caspase-8/Bid activation and apoptosis are dependent on the activation of the MAPK/Erk pathway. Together, our results provide evidence that HLA-DR signaling activates the MAPK/Erk pathway in A375 melanoma cells, which has a functional role in the resistance of these cells to Fas-mediated apoptosis. These observations underline the potential importance that HLA-DR signaling might have in melanoma immune escape and tumor progression.