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Adenovirus expressing β2-microglobulin recovers HLA class I expression and antitumor immunity by increasing T-cell recognition

Cancer Gene Therapy volume 21, pages 317–332 (2014)Cite this article

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Abstract

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.

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Acknowledgements

We thank Dr Concepción Delgado from Regional Blood Transfusion Center for providing healthy donor peripheral blood samples. This work was supported by the Consejeraía Andaluza de Salud (SAS, project PI 09/0382 to NA), Fondo de Investigaciones Sanitarias, ISCII (FIS, PI11/01022), Red Genómica del Cáncer (RETIC RD 06/0020), Plan Andaluz de Investigación (Group CTS 143), Biobank Projects (RD 09/0076/00165 and PI13/0010/0039) and Proyecto de Excelencia de Consejería de Inovación (CTS 03,952 and CVI 4740). This study was also supported by the European Network for the identification and validation of antigens and biomarkers in cancer and their application in clinical tumor immunology (ENACT) project (European community LSHC-CT-2004–503306). NA has I3 SNS research contract supported by FPS and ISCIII.

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Authors and Affiliations

  1. Department of Clinical Analysis and Immunology, UGC Laboratorio Clinico, University Hospital Virgen de las Nieves, Granada, Spain

    A B del Campo, J Carretero, S Zinchenko, F Ruiz-Cabello, F Garrido & N Aptsiauri

  2. Department of Biochemistry, Molecular Biology III and Immunology, University of Granada Medical School, Granada, Spain

    A B del Campo, J Carretero, F Ruiz-Cabello & F Garrido

  3. Microscopy and Cytometry Research Unit, San Cecilio University Hospital, Granada, Spain

    J A Muñoz

  4. Division of Hepatology and Gene Therapy, Center for Applied Medical Research (CIMA), University of Navarra Medical School, Pamplona, Spain

    G González-Aseguinolaza

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  1. A B del Campo
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Correspondence to N Aptsiauri.

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del Campo, A., Carretero, J., Muñoz, J. et al. Adenovirus expressing β2-microglobulin recovers HLA class I expression and antitumor immunity by increasing T-cell recognition. Cancer Gene Ther 21, 317–332 (2014). https://doi.org/10.1038/cgt.2014.32

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