Epigenetic enhancement of antigen processing and presentation promotes immune recognition of tumors.
Histone deacetylase inhibitors (HDACi) have been hailed as a powerful new class of anticancer drugs. The HDACi, trichostatin A (TSA), is thought to interfere with epigenetic control of cell cycle progression in G1 and G2-M phase, resulting in growth arrest, differentiation, or apoptosis. Here, we describe a novel mechanism of action of HDACis in promoting immune responses against tumors. We report that treatment of carcinoma cells with TSA increases the expression of many components of the antigen processing machinery, including TAP-1, TAP-2, LMP-2, and Tapasin. Consistent with this result, we found that treatment of metastatic carcinoma cells with TSA also results in an increase in MHC class I expression on the cell surface that functionally translates into an enhanced susceptibility to killing by antigen-specific CTLs. Finally, we observed that TSA treatment suppresses tumor growth and increases tap-1 promoter activity in TAP-deficient tumor cells in vivo. Intriguingly, this in vivo anti-tumoral effect of TSA is entirely mediated by an increase in immunogenicity of the tumor cells, as it does not occur in immunodeficient mice. These novel insights into the molecular mechanisms controlling tumor immune escape may help revise immunotherapeutic modalities for eradicating cancers.
Setiadi
A Francesca
AF
Biomedical Research Centre, Michael Smith Laboratories, Department of Zoology, University of British Columbia, Vancouver, British Columbia, Canada.
Omilusik
Kyla
K
David
Muriel D
MD
Seipp
Robyn P
RP
Hartikainen
Jennifer
J
Gopaul
Rayshad
R
Choi
Kyung Bok
KB
Jefferies
Wilfred A
WA
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D044127:Epigenesis, Genetic / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; D004791:Enzyme Inhibitors; D015395:Histocompatibility Antigens Class I; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D026901:Membrane Transport Proteins; D012333:RNA, Messenger; C486171:Tap1 protein, mouse; C489516:Tap2 protein, mouse; C107762:tapasin; C012589:trichostatin A; D012319:RNA Polymerase II