Rouas-Freiss Nathalie, Bruel Sylvie, Menier Catherine, Marcou Céline, Moreau Philippe, Carosella Edgardo D
Service de Recherches en Hémato-Immunologie, CEA-DSV-DRM, Hôpital Saint-Louis, IUH, Paris, France.
Int J Cancer. 2005 Oct 20;117(1):114-22. doi: 10.1002/ijc.21151.
Considerable information has been accumulated on HLA-G expression in tumor lesions in which HLA-G is viewed as a way to turn off anti-tumoral immunity. Nevertheless, there is little data concerning the mechanisms by which expression and function of HLA-G are regulated in malignant cells. Here, we have addressed these points by studying a melanoma cell line derived from a surgically-removed HLA-G-positive melanoma lesion. We show that HLA-G expression in melanoma cells can be regulated at the mRNA splicing level. Indeed, melanoma cells rapidly switched from cell-surface HLA-G1 to intra-cellular HLA-G2 expression. This mechanism restored tumor sensitivity to NK lysis. Moreover, switch from HLA-G1 to HLA-G2 was strong enough to prevent re-expression of immunoprotective HLA-G1 even following treatments with cytokines and DNA demethylating agent. Modulating HLA-G at the mRNA splicing level would be an efficient way of lifting in vivo HLA-G-mediated tumor immune escape.
关于肿瘤病变中HLA - G表达已积累了大量信息，其中HLA - G被视为一种关闭抗肿瘤免疫的方式。然而，关于恶性细胞中HLA - G表达和功能的调控机制的数据却很少。在此，我们通过研究源自手术切除的HLA - G阳性黑色素瘤病变的黑色素瘤细胞系来解决这些问题。我们表明，黑色素瘤细胞中HLA - G的表达可在mRNA剪接水平受到调控。实际上，黑色素瘤细胞迅速从细胞表面HLA - G1表达转变为细胞内HLA - G2表达。这种机制恢复了肿瘤对NK细胞裂解的敏感性。此外，从HLA - G1到HLA - G2的转变足够强烈，即使在用细胞因子和DNA去甲基化剂处理后，也能阻止免疫保护性HLA - G1的重新表达。在mRNA剪接水平调节HLA - G将是一种有效解除体内HLA - G介导的肿瘤免疫逃逸的方法。
