Research Papers: Immunology:
Proteomic analysis uncovers common effects of IFN-γ and IL-27 on the HLA class I antigen presentation machinery in human cancer cells
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Andrea Petretto1,*, Grazia Carbotti2,*, Elvira Inglese1, Chiara Lavarello1, Maria Pia Pistillo3, Valentina Rigo2, Michela Croce2, Luca Longo2, Stefania Martini2, Paola Vacca2,4, Silvano Ferrini2,* and Marina Fabbi2,*
1 Core Facilities-Proteomics Laboratory, Istituto Giannina Gaslini, Genoa, Italy
2 Department of Integrated Oncological Therapies, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
3 Tumor Epigenetics Unit, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
4 Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy
* These authors have equally contributed to this work
Silvano Ferrini, email:
Marina Fabbi, email:
Keywords: IL-27, IFN-γ, proteomic analysis, HLA class I, cancer cells, Immunology and Microbiology Section, Immune response, Immunity
Received: July 10, 2016 Accepted: September 17, 2016 Published: September 24, 2016
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.
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