Mohr S, Neuville A, Bottin M C, Micillino J C, Keith G, Rihn B H
Institut National de Recherche et de Sécurité, Avenue de Bourgogne, BP27, 54501 Vandoeuvre.
Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, UPR 9002, Rue René Descartes, 67084 Strasbourg.
Cancer Genomics Proteomics. 2005 May-Jun;2(3):125-135. Epub 2005 May 1.
Malignant pleural mesothelioma (MPM) is a highly malignant tumor arising in patients previously exposed to asbestos fibers. Its increasing incidence and its social, financial and human impact have become a frequent problem in many industrialized countries. The unresponsiveness of malignant mesothelioma to conventional therapies has led clinicians to develop new treatments. As immunotherapy has been shown to offer promising and targeted treatment of MPM patients, the knowledge of the immunoresistance level of MPM may be a valuable tool for "à la carte" therapy. In a previous work, we profiled the gene expression of two MPM tissues compared to healthy mesothelial cells using a 10K cDNA microarray. Subsequent clustering analysis identified several clusters of differentially-expressed genes among those that are functionally-related to the immune system. In this report, we focus on genes with expression changes that may facilitate tumor escape from immune-mediated rejection. We also analyzed the immune reaction by staining the immunocompetent cells surrounding the tumor. Interestingly, the tumor with the strongest escape response, as shown by the expression of numerous immunoresistance-associated genes, displayed the strongest T cell infiltrate. The main genes conferring immunoresistance are CD74, HLADOA, HLADMB, PTGS1, IGFBP7 and TGFB3, by favoring immune tolerance, and CFLAR, DFFA, TNFRSF6, BNIP3L by impairing apoptosis. These observations have fundamental consequences in the understanding of immunological properties of MPM, and offer a new insight into the mechanisms whereby MPM may circumvent host-mediated immune activities and promotes its own development. For an immunomodulation strategy to cure mesothelioma, it is crucial to characterize the MPM "immune signature" to design adapted immunotherapies.
恶性胸膜间皮瘤（MPM）是一种高度恶性肿瘤，发生于既往接触过石棉纤维的患者。其发病率不断上升，以及对社会、经济和人力的影响，已成为许多工业化国家常见的问题。恶性间皮瘤对传统疗法无反应，促使临床医生研发新的治疗方法。由于免疫疗法已被证明可为MPM患者提供有前景的靶向治疗，了解MPM的免疫抵抗水平可能是“量身定制”疗法的宝贵工具。在之前的一项研究中，我们使用10K cDNA微阵列分析了两个MPM组织与健康间皮细胞的基因表达情况。随后的聚类分析在与免疫系统功能相关的基因中鉴定出了几个差异表达基因簇。在本报告中，我们重点关注那些表达变化可能有助于肿瘤逃避免疫介导排斥反应的基因。我们还通过对肿瘤周围免疫活性细胞进行染色来分析免疫反应。有趣的是，如众多免疫抵抗相关基因的表达所示，具有最强逃避反应的肿瘤显示出最强的T细胞浸润。赋予免疫抵抗的主要基因是通过促进免疫耐受的CD74、HLADOA、HLADMB、PTGS1、IGFBP7和TGFB3，以及通过损害细胞凋亡的CFLAR、DFFA、TNFRSF6、BNIP3L。这些观察结果对理解MPM的免疫学特性具有重要意义，并为MPM规避宿主介导的免疫活动并促进自身发展的机制提供了新的见解。对于治愈间皮瘤的免疫调节策略而言，表征MPM的“免疫特征”以设计合适的免疫疗法至关重要。
