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Implication of the β2-microglobulin gene in the generation of tumor escape phenotypes

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Abstract

Classical MHC molecules present processed peptides from endogenous protein antigens on the cell surface, which allows CD8+ cytotoxic T lymphocytes (CTLs) to recognize and respond to the abnormal antigen repertoire of hazardous cells, including tumor cells. The light chain, β2-microglobulin (β2m), is an essential constant component of all trimeric MHC class I molecules. There is convincing evidence that β2m deficiency generates immune escape phenotypes in different tumor entities, with an exceptionally high frequency in colorectal carcinoma (CRC) and melanoma. Damage of a single β2m gene by LOH on chromosome 15 may be sufficient to generate a tumor cell precommitted to escape. In addition, this genetic lesion is followed in some tumors by a mutation of the second gene (point mutation or insertion/deletion), which produces a tumor cell unable to express any HLA class I molecule. The pattern of mutations found in microsatellite unstable colorectal carcinoma (MSI-H CRC) and melanoma showed a striking similarity, namely the predominance of frameshift mutations in repetitive CT elements. This review emphasizes common but also distinct molecular mechanisms of β2m loss in both tumor types. It also summarizes recent studies that point to an acquired β2m deficiency in response to cancer immunotherapy, a barrier to successful vaccination or adoptive cellular therapy.

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Abbreviations

β2m:

β2-microglobulin

CRC:

Colorectal cancer

HLA:

Human leukocyte antigen

MHC:

Major histocompatibility complex

LOH:

Loss of heterozygosity

MMR:

Mismatch repair

MSI-H:

High microsatellite instability

MSS:

Microsatellite stability

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Acknowledgments

The authors are grateful to Dr Natalia Aptsiauri for helpful discussions and suggestions, to Dr Isabel Maleno for helping in the preparation of the manuscript, and to Eva García and Ana Isabel Rodríguez for technical assistance. They also thank the Tumor-Tissue Biobank of Virgen de las Nieves University Hospital for providing samples. The study was partially supported by grants from the Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Red Genómica del Cáncer (RETICRD 06/020), Consejería de Salud de la Junta de Andalucía, Consejería de Innovación, Ciencia y Empresa Junta de Andalucía, (P08-TIC-4299), Dirección General de Investigación y Gestión del Plan Nacional I + D + i (TIN2009-13489), Proyecto de Investigación de Excelencia (CTS-3952, CVI-4740 and P06/-CTS-02200), and Plan Andaluz de Investigación (PAI, Group CTS) in Spain; and from the European Searchable Tumour Cell Line Database (ESTDAB) project (contract No. QLRI-CT-2001-01325) at http://www.ebi.ac.uk/estdab, 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), and the Cancer Immunotherapy project (European community OJ 2004/c158,18234) and the Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF) “Alliance on Immunotherapy of Cancer”.

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The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Servicio de Análisis Clínicos e Inmunología, Hospital Universitario Virgen de las Nieves, Avda. Fuerzas Armadas s/n, 18014, Granada, Spain

    Monica Bernal, Francisco Ruiz-Cabello & Federico Garrido

  2. Departamento de Bioquímica, Biología Molecular III e Inmunología, Facultad de Medicina, Granada, Spain

    Francisco Ruiz-Cabello & Federico Garrido

  3. Servicio de Anatomía Patológica, Hospital Universitario Virgen de las Nieves, Granada, Spain

    Angel Concha

  4. Department of Dermatologie, University Hospital, Essen, Germany

    Annette Paschen

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  1. Monica Bernal
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  2. Francisco Ruiz-Cabello
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  3. Angel Concha
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  4. Annette Paschen
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  5. Federico Garrido
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Correspondence to Federico Garrido.

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Bernal, M., Ruiz-Cabello, F., Concha, A. et al. Implication of the β2-microglobulin gene in the generation of tumor escape phenotypes. Cancer Immunol Immunother 61, 1359–1371 (2012). https://doi.org/10.1007/s00262-012-1321-6

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