Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells

Andrea Petretto, Grazia Carbotti, Elvira Inglese, Chiara Lavarello, Maria Pia Pistillo, Valentina Rigo, Michela Croce, Luca Longo, Stefania Martini, Paola Vacca, Silvano Ferrini, Marina Fabbi

Research output: Contribution to journalArticle

Abstract

IL-27, a member of the IL-12-family of cytokines, has shown anti-tumor activity in several pre-clinical models due to anti-proliferative, anti-angiogenic and immune-enhancing effects. On the other hand, IL-27 demonstrated immune regulatory activities and inhibition of auto-immunity in mouse models. Also, we reported that IL-27, similar to IFN-γ, induces the expression of IL-18BP, IDO and PD-L1 immune regulatory molecules in human cancer cells. Here, a proteomic analysis reveals that IL-27 and IFN-γ display a broad overlap of functions on human ovarian cancer cells. Indeed, among 990 proteins modulated by either cytokine treatment in SKOV3 cells, 814 showed a concordant modulation by both cytokines, while a smaller number (176) were differentially modulated. The most up-regulated proteins were common to both IFN-γ and IL-27. In addition, functional analysis of IL-27-regulated protein networks highlighted pathways of interferon signaling and regulation, antigen presentation, protection from natural killer cell-mediated cytotoxicity, regulation of protein polyubiquitination and proteasome, aminoacid catabolism and regulation of viral protein levels. Importantly, we found that IL-27 induced HLA class I molecule expression in human cancer cells of different histotypes, including tumor cells showing very low expression. IL-27 failed only in a cancer cell line bearing a homozygous deletion in the B2M gene. Altogether, these data point out to a broad set of activities shared by IL-27 and IFN-γ, which are dependent on the common activation of the STAT1 pathway. These data add further explanation to the anti-tumor activity of IL-27 and also to its dual role in immune regulation.

Original languageEnglish
Pages (from-to)72518-72536
Number of pages19
JournalOncotarget
Volume7
Issue number45
DOIs
Publication statusPublished - 2016

    Fingerprint

Keywords

  • Cancer cells
  • HLA class I
  • IFN-γ
  • IL-27
  • Immune response
  • Immunity
  • Immunology and Microbiology Section
  • Proteomic analysis

ASJC Scopus subject areas

  • Oncology

Cite this

Petretto, A., Carbotti, G., Inglese, E., Lavarello, C., Pistillo, M. P., Rigo, V., Croce, M., Longo, L., Martini, S., Vacca, P., Ferrini, S., & Fabbi, M. (2016). Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells. Oncotarget, 7(45), 72518-72536. https://doi.org/10.18632/oncotarget.12235