title: Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma.
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.
authors.affiliation: 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.
authors.forename: Ana B
authors.initials: AB
authors.lastname: del Campo
authors.forename: Jon Amund
authors.initials: JA
authors.lastname: Kyte
authors.forename: Javier
authors.initials: J
authors.lastname: Carretero
authors.forename: Svitlana
authors.initials: S
authors.lastname: Zinchencko
authors.forename: Rosa
authors.initials: R
authors.lastname: Méndez
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
authors.forename: Francisco
authors.initials: F
authors.lastname: Ruiz-Cabello
authors.forename: Steinar
authors.initials: S
authors.lastname: Aamdal
authors.forename: Gustav
authors.initials: G
authors.lastname: Gaudernack
authors.forename: Federico
authors.initials: F
authors.lastname: Garrido
authors.forename: Natalia
authors.initials: N
authors.lastname: Aptsiauri
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008545:Melanoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019139:Tumor Escape / Q000235:genetics* / Q000276:immunology; D001613:beta 2-Microglobulin / Q000235:genetics* / Q000276:immunology
chemical_list: D015395:Histocompatibility Antigens Class I; D001613:beta 2-Microglobulin
keywords: beta2-microglobulin mutation; immune escape; metastatic melanoma; tumor HLA class I loss