Multiple structural and epigenetic defects in the human leukocyte antigen class I antigen presentation pathway in a recurrent metastatic melanoma following immunotherapy

Chien Chung Chang, Giuseppe Pirozzi, Shao Hsuan Wen, I. Hsin Chung, Bau Lin Chiu, Simona Errico, Monica Luongo, Maria Luisa Lombardi, Soldano Ferrone

Research output: Contribution to journalArticlepeer-review

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 (TAPBP684delA) 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.

Original languageEnglish
Pages (from-to)26562-26575
Number of pages14
JournalJournal of Biological Chemistry
Volume290
Issue number44
DOIs
Publication statusPublished - Oct 30 2015

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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