title: Multiple structural and epigenetic defects in the human leukocyte antigen class I antigen presentation pathway in a recurrent metastatic melanoma following immunotherapy.
abstract: Scant information is available about the molecular basis of multiple HLA class I antigen-processing machinery defects in malignant cells, although this information contributes to our understanding of the molecular immunoescape mechanisms utilized by tumor cells and may suggest strategies to counteract them. In the present study we reveal a combination of IFN-γ-irreversible structural and epigenetic defects in HLA class I antigen-processing machinery in a recurrent melanoma metastasis after immunotherapy. These defects include loss of tapasin and one HLA haplotype as well as selective silencing of HLA-A3 gene responsiveness to IFN-γ. Tapasin loss is caused by a germ-line frameshift mutation in exon 3 (TAPBP(684delA)) along with a somatic loss of the other gene copy. Selective silencing of HLA-A3 gene and its IFN-γ responsiveness is associated with promoter CpG methylation nearby site-α and TATA box, reversible after DNA methyltransferase 1 depletion. This treatment combined with tapasin reconstitution and IFN-γ stimulation restored the highest level of HLA class I expression and its ability to elicit cytotoxic T cell responses. These results represent a novel tumor immune evasion mechanism through impairing multiple components at various levels in the HLA class I antigen presentation pathway. These findings may suggest a rational design of combinatorial cancer immunotherapy harnessing DNA demethylation and IFN-γ response.
authors.affiliation: From the Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan 30013, ccchang@life.nthu.edu.tw.
authors.forename: Chien-Chung
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Experimental Oncology, National Cancer Institute, Naples 80131, Italy, and.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pirozzi
authors.affiliation: From the Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan 30013.
authors.forename: Shao-Hsuan
authors.initials: SH
authors.lastname: Wen
authors.affiliation: From the Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan 30013.
authors.forename: I-Hsin
authors.initials: IH
authors.lastname: Chung
authors.affiliation: From the Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan 30013.
authors.forename: Bau-Lin
authors.initials: BL
authors.lastname: Chiu
authors.affiliation: Department of Experimental Oncology, National Cancer Institute, Naples 80131, Italy, and.
authors.forename: Simona
authors.initials: S
authors.lastname: Errico
authors.affiliation: Department of Experimental Oncology, National Cancer Institute, Naples 80131, Italy, and.
authors.forename: Monica
authors.initials: M
authors.lastname: Luongo
authors.affiliation: Department of Experimental Oncology, National Cancer Institute, Naples 80131, Italy, and.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Lombardi
authors.affiliation: Departments of Surgery and of Orthopedic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
mesh_terms: D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000276:immunology; D019175:DNA Methylation / Q000235:genetics / Q000276:immunology; D016368:Frameshift Mutation; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D020868:Gene Silencing / Q000276:immunology*; D015791:HLA-A3 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D026901:Membrane Transport Proteins / Q000235:genetics / Q000276:immunology; D009364:Neoplasm Recurrence, Local; D019139:Tumor Escape
chemical_list: D015791:HLA-A3 Antigen; C573415:IFNG protein, human; D026901:Membrane Transport Proteins; C107762:tapasin; D007371:Interferon-gamma
keywords: DNA methylation; antigen presentation; immunotherapy; major histocompatibility complex (MHC); tumor immunology