Del Campo A B, Carretero J, Muñoz J A, Zinchenko S, Ruiz-Cabello F, González-Aseguinolaza G, Garrido F, Aptsiauri N
1] Department of Clinical Analysis and Immunology, UGC Laboratorio Clinico, University Hospital Virgen de las Nieves, Granada, Spain [2] Department of Biochemistry, Molecular Biology III and Immunology, University of Granada Medical School, Granada, Spain.
Microscopy and Cytometry Research Unit, San Cecilio University Hospital, Granada, Spain.
Cancer Gene Ther. 2014 Aug;21(8):317-32. doi: 10.1038/cgt.2014.32. Epub 2014 Jun 27.
Optimal tumor cell surface expression of human leukocyte antigen (HLA) class I molecules is essential for the presentation of tumor-associated peptides to T-lymphocytes. However, a hallmark of many types of tumor is the loss or downregulation of HLA class I expression associated with ineffective tumor antigen presentation to T cells. Frequently, HLA loss can be caused by structural alterations in genes coding for HLA class I complex, including the light chain of the complex, β2-microglobulin (β2m). Its best-characterized function is to interact with HLA heavy chain and stabilize the complex leading to a formation of antigen-binding cleft recognized by T-cell receptor on CD8+ T cells. Our previous study demonstrated that alterations in the β2m gene are frequently associated with cancer immune escape leading to metastatic progression and resistance to immunotherapy. These types of defects require genetic transfer strategies to recover normal expression of HLA genes. Here we characterize a replication-deficient adenoviral vector carrying human β2m gene, which is efficient in recovering proper tumor cell surface HLA class I expression in β2m-negative tumor cells without compromising the antigen presentation machinery. Tumor cells transduced with β2m induced strong activation of T cells in a peptide-specific HLA-restricted manner. Gene therapy using recombinant adenoviral vectors encoding HLA genes increases tumor antigen presentation and represents a powerful tool for modulation of tumor cell immunogenicity by restoration of missing or altered HLA genes. It should be considered as part of cancer treatment in combination with immunotherapy.
人白细胞抗原（HLA）I类分子在肿瘤细胞表面的最佳表达对于向T淋巴细胞呈递肿瘤相关肽至关重要。然而，许多类型肿瘤的一个标志是HLA I类表达的缺失或下调，这与肿瘤抗原向T细胞的呈递无效有关。通常，HLA缺失可能是由编码HLA I类复合物的基因结构改变引起的，包括该复合物的轻链β2-微球蛋白（β2m）。其最具特征的功能是与HLA重链相互作用并稳定该复合物，从而形成CD8+T细胞上T细胞受体识别的抗原结合裂隙。我们之前的研究表明，β2m基因的改变常与癌症免疫逃逸相关，导致转移进展和对免疫治疗的抗性。这些类型的缺陷需要基因转移策略来恢复HLA基因的正常表达。在此，我们对携带人β2m基因的复制缺陷型腺病毒载体进行了表征，该载体能有效地在β2m阴性肿瘤细胞中恢复适当的肿瘤细胞表面HLA I类表达，而不会损害抗原呈递机制。用β2m转导的肿瘤细胞以肽特异性HLA限制的方式诱导T细胞的强烈激活。使用编码HLA基因的重组腺病毒载体进行基因治疗可增加肿瘤抗原呈递，并且是通过恢复缺失或改变的HLA基因来调节肿瘤细胞免疫原性的有力工具。它应被视为与免疫疗法联合的癌症治疗的一部分。
