Immunotherapy augments the effect of 5-azacytidine on HPV16-associated tumours with different MHC class I-expression status

Abstract

Background:Epigenetic mechanisms have important roles in the tumour escape from immune responses, such as in MHC class I downregulation or altered expression of other components involved in antigen presentation. Chemotherapy with DNA methyltransferase inhibitors (DNMTi) can thus influence the tumour cell interactions with the immune system and their sensitivity to immunotherapy.Methods:We evaluated the therapeutic effects of the DNMTi 5-azacytidine (5AC) against experimental MHC class I-deficient and -positive tumours. The 5AC therapy was combined with immunotherapy, using a murine model for HPV16-associated tumours.Results:We have demonstrated 5AC additive effects against MHC class I-positive and -deficient tumours when combined with unmethylated CpG oligodeoxynucleotides or with IL-12-producing cellular vaccine. The efficacy of the combined chemoimmunotherapy against originally MHC class I-deficient tumours was partially dependent on the CD8+-mediated immune responses. Increased cell surface expression of MHC class I cell molecules, associated with upregulation of the antigen-presenting machinery-related genes, as well as of genes encoding selected components of the IFNγ-signalling pathway in tumours explanted from 5AC-treated animals, were observed.Conclusion:Our data suggest that chemotherapy of MHC class I-deficient tumours with 5AC combined with immunotherapy is an attractive setting in the treatment of MHC class I-deficient tumours.

DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment

“…We have reported previously that 5AC had an antitumor effect when used for treatment of early growing but not established murine HPVassociated TC-1/A9 tumors [25]. In this study, we have shown that 5AC is also effective for treatment of early and contrary to TC-1/A9, established TRAMP-C2 cells of adenocarcinoma mouse prostate model.…”

Alterations of immune response of non-small cell lung cancer with Azacytidine

“…A second key issue for immune cell interaction with tumor cells is that, in vivo , AZA administration to tumor-bearing mice has been shown to induce antigen processing and presentation genes, particularly when administered with CpG TLR9 agonists, and this is largely attributed to interferon-γ production by lymphocytes [13]. While the lymphocyte-specific γ-interferon is not induced in NSCLC lines with AZA treatment, there is up-regulation of the interferon-γ receptor ( IFNGR1 ) as well as of multiple STAT genes, including STAT1 , the major IFNGR1 signal transducer (Fig.…”

The urgent need to recover MHC class I in cancers for effective immunotherapy

“…An attractive strategy for the restoration of MHC-I expression is by epigenetic modifiers, like inhibitors of DNA methyltransferase (DNMT) or histone deacetylase (HDAC). In several recent papers, such regulation at the epigenetic level was shown to be able to synergize with immunotherapy for the eradication of mouse tumor models [48, 49, 50•]. Interestingly, IFN-γ-induced restoration of ‘soft’ lesions of MHC-I, one of the most powerful inducers of this gene, was shown to partly mediate its effect by inducing demethylation of antigen-processing machinery related genes, including the TAP genes and LMP-2 [51].…”