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

Int J Cancer. 2014 Jan 1;134(1):102-13. doi: 10.1002/ijc.28338. Epub 2013 Jul 16.

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.

Keywords: beta2-microglobulin mutation; immune escape; metastatic melanoma; tumor HLA class I loss.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Line, Tumor
  • Flow Cytometry
  • Histocompatibility Antigens Class I / biosynthesis*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / immunology
  • Humans
  • Immunohistochemistry
  • Loss of Heterozygosity
  • Melanoma / genetics*
  • Melanoma / immunology
  • Melanoma / pathology
  • Mutation
  • Neoplasm Invasiveness / genetics
  • Neoplasm Invasiveness / pathology
  • Neoplasm Metastasis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Escape / genetics*
  • Tumor Escape / immunology
  • beta 2-Microglobulin / genetics*
  • beta 2-Microglobulin / immunology

Substances

  • Histocompatibility Antigens Class I
  • beta 2-Microglobulin