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      Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma.

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          Abstract

          Cancer cells escape T-cell-mediated destruction by losing human leukocyte antigen (HLA) class I expression via various mechanisms, including loss of beta2-microglobulin (β2m). Our study illustrates the immune escape of HLA class I-negative tumor cells and chronological sequence of appearance of tumor β2m gene mutation in successive lesions obtained from a patient with metastatic melanoma. We observed a gradual decrease in HLA expression in consecutive lesions with few HLA-negative nodules in the primary tumor and the emergence of a totally negative lesion at later stages of the disease. We detected loss of β2m in β2m-negative nests of the primary tumor caused by a combination of two alterations: (i) a mutation (G to T substitution) in codon 67 in exon 2 of β2m gene, producing a stop codon and (ii) loss of the second gene copy by loss of heterozygosity (LOH) in chromosome 15. The same β2m mutation was found in a homogeneously β2m-negative metastasis 10 months later and in a cell line established from a biopsy of a postvaccination lymph node. Microsatellite analysis revealed the presence of LOH in chromosomes 6 and 15 in tumor samples, showing an accumulation of chromosomal loss at specific short tandem repeats in successive metastases during disease progression. HLA loss correlated with decreased tumor CD8+ T-cell infiltration. Early incidence of β2m defects can cause an immune selection and expansion of highly aggressive melanoma clones with irreversible genetic defects causing total loss of HLA class I expression and should be taken into consideration as a therapeutic target in the development of cancer immunotherapy protocols.

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          Author and article information

          Journal
          Int. J. Cancer
          International journal of cancer
          1097-0215
          0020-7136
          Jan 1 2014
          : 134
          : 1
          Affiliations
          [1 ] Department of Clinical Analysis and Immunology, University Hospital Virgen de las Nieves, Granada, Spain; Department of Biochemistry, Molecular Biology III and Immunology, University of Granada Medical School, Granada, Spain.
          Article
          10.1002/ijc.28338
          23784959
          © 2013 UICC.

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