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


CONCLUSIONS
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.
Department of Tumour Immunology, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Videnska 1083, Prague 4 14220, Czech Republic.
J
J
Símová
V
V
Polláková
M
M
Indrová
R
R
Mikyšková
J
J
Bieblová
I
I
Stěpánek
J
J
Bubeník
M
M
Reiniš
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D052162:Human papillomavirus 16 / Q000302:isolation & purification*; D007167:Immunotherapy; D008297:Male; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000628:therapy* / Q000821:virology; D060888:Real-Time Polymerase Chain Reaction
D000964:Antimetabolites, Antineoplastic; D017931:DNA Primers; D015395:Histocompatibility Antigens Class I; D001374:Azacitidine