Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany.
Int J Cancer. 2010 Sep 1;127(5):1001-10. doi: 10.1002/ijc.25283.
Colorectal cancers (CRC) develop through 2 major pathways of genetic instability. In contrast to the majority of CRCs, which are characterized by chromosomal instability, high-level microsatellite unstable (MSI-H) CRCs arise as a consequence of the loss of DNA mismatch repair (MMR) functions and show accumulation of insertion and deletion mutations particularly in microsatellite sequences. MSI-H occurs in about 15% of CRCs, and virtually all CRCs occurring in the context of the hereditary cancer-predisposing Lynch syndrome. These tumors are characterized by a comparably good prognosis and a low frequency of distant metastases. Because of the expression of a defined set of tumor-specific antigens, MSI-H CRCs elicit a strong local and systemic antitumoral immune response of the host and therefore use different strategies to evade the control of the immune system. In this review, we will summarize novel molecular mechanisms that at the same time drive pathogenesis, immunogenicity and immune evasion during the development and progression of MSI-H CRCs. We will focus on the current knowledge about alterations in human leukocyte antigen (HLA) antigen presentation and discuss how immune evasion-while offering protection against local antitumoral immune responses-paradoxically might interfere with the ability of the tumor to form distant organ metastases.
结直肠癌（CRC）通过 2 种主要的遗传不稳定途径发展。与大多数具有染色体不稳定性的 CRC 不同，高水平微卫星不稳定（MSI-H）CRC 是由于 DNA 错配修复（MMR）功能丧失而产生的，并且表现出插入和缺失突变的积累，特别是在微卫星序列中。MSI-H 发生在约 15%的 CRC 中，几乎所有发生在遗传性癌症易感 Lynch 综合征背景下的 CRC 都是如此。这些肿瘤具有相对较好的预后和低远处转移频率。由于表达一组明确的肿瘤特异性抗原，MSI-H CRC 引发宿主强烈的局部和全身抗肿瘤免疫反应，因此它们使用不同的策略来逃避免疫系统的控制。在这篇综述中，我们将总结同时驱动 MSI-H CRC 发病机制、免疫原性和免疫逃逸的新的分子机制。我们将重点介绍关于人类白细胞抗原（HLA）抗原呈递的改变的最新知识，并讨论免疫逃逸——虽然提供了对局部抗肿瘤免疫反应的保护——如何矛盾地可能干扰肿瘤形成远处器官转移的能力。
