del Campo A B, Carretero J, Aptsiauri N, Garrido F
Servicio de Análisis Clínicos, Hospital Universitario Virgen de las Nieves, Granada, Spain.
Tissue Antigens. 2012 Mar;79(3):147-54. doi: 10.1111/j.1399-0039.2011.01831.x.
The dynamic interaction between the host immune system and growing cancer has been of central interest to the field of tumor immunology over the past years. Recognition of tumor-associated antigens (TAA) by self-HLA (human leukocyte antigen) class I-restricted CD8+ T cells is a main feature in the detection and destruction of malignant cells. The discovery and molecular characterization of TAA has changed the field of cancer treatment and introduced a new era of cancer immunotherapy aimed at increasing tumor immunogenicity and T-cell-mediated anti-tumor immunity. Unfortunately, while these new protocols of cancer immunotherapy are mediating induction of tumor-specific T lymphocytes in patients with certain malignancies, they have not yet delivered substantial clinical benefits, such as induction of tumor regression or increased disease-free survival. It has become apparent that lack of tumor rejection is the result of immune selection and escape by tumor cells that develop low immunogenic phenotypes. Substantial experimental data support the existence of a variety of different mechanisms involved in the tumor escape phase, including loss or downregulation of HLA class I antigens. These alterations could be caused by regulatory ('soft') or by structural/irreversible ('hard') defects. On the basis of the evidence obtained from experimental mouse cancer models and metastatic human tumors, the structural defects underlying HLA class I loss may have profound implications on T-cell-mediated tumor rejection and ultimately on the outcome of cancer immunotherapy. Strategies to overcome this obstacle, including gene therapy to recover normal expression of HLA class I genes, require consideration. In this review, we outline the importance of monitoring and correction of HLA class I alterations during cancer development and immunotherapy.
在过去几年中，宿主免疫系统与不断生长的肿瘤之间的动态相互作用一直是肿瘤免疫学领域的核心研究兴趣点。自我人类白细胞抗原（HLA）I类限制性CD8 + T细胞对肿瘤相关抗原（TAA）的识别是检测和破坏恶性细胞的主要特征。TAA的发现和分子特征改变了癌症治疗领域，并引入了一个旨在提高肿瘤免疫原性和T细胞介导的抗肿瘤免疫的癌症免疫治疗新时代。不幸的是，虽然这些新的癌症免疫治疗方案正在某些恶性肿瘤患者中诱导肿瘤特异性T淋巴细胞，但它们尚未带来实质性的临床益处，如诱导肿瘤消退或延长无病生存期。显然，缺乏肿瘤排斥是肿瘤细胞免疫选择和逃逸的结果，这些肿瘤细胞形成了低免疫原性表型。大量实验数据支持肿瘤逃逸阶段存在多种不同机制，包括HLA I类抗原的缺失或下调。这些改变可能由调节性（“软性”）或结构性/不可逆性（“硬性”）缺陷引起。基于从实验性小鼠癌症模型和转移性人类肿瘤获得的证据，HLA I类缺失背后的结构性缺陷可能对T细胞介导的肿瘤排斥以及最终对癌症免疫治疗的结果产生深远影响。克服这一障碍的策略，包括恢复HLA I类基因正常表达的基因治疗，需要加以考虑。在本综述中，我们概述了在癌症发展和免疫治疗过程中监测和纠正HLA I类改变的重要性。
