Differential effects of low-dose decitabine on immune effector and suppressor responses in melanoma-bearing mice.
BACKGROUND
Low doses of the demethylating agent decitabine have been shown to enhance the sensitivity of tumors to immune effector cells and molecules through upregulation of tumor antigen presentation and apoptotic pathways. Effects on host immune effector and suppressor responses have not been well characterized.


METHODS
Mice bearing B16 melanoma were treated with low-dose decitabine, cytokine, interleukin-2 (IL-2), toll-like receptor 9 agonist ODN1826, and/or a viral vectored vaccine targeting the melanoma antigen Trp2. Lymphoid and myeloid effector and suppressor cells were examined both systemically and intratumorally with functional, flow cytometric, and polymerase chain reaction-based assays.


RESULTS
Enhancement of tumor growth delay was observed when decitabine was applied sequentially but not concurrently with IL-2. In contrast, complete responses and prolonged survival were observed when decitabine was applied with ODN1826 as therapy and with ODN1826 as a Trp2 vaccine adjuvant. Decitabine decreased natural killer and antigen-specific cellular immune responses when administered concurrently with IL-2 and with ODN1826; the Th1-associated transcription factor Tbet also decreased. T regulatory cells were not affected. When applied concurrently with ODN1826, decitabine increased macrophage cytotoxicity, M1 polarization, and dendritic cell activation. Myeloid-derived suppressor cells were reduced.


CONCLUSIONS
Low-dose decitabine promotes both anti- and pro-tumor host immune responses to immunotherapeutics in melanoma-bearing mice. Macrophage effector and dendritic cell activation increase, and myeloid suppressor cells decrease. Lymphoid effector responses, however, can be inhibited.
Taussig Cancer Institute, R40, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. triozzp@ccf.org
Pierre L
PL
Triozzi
Wayne
W
Aldrich
Susan
S
Achberger
Selvarangan
S
Ponnazhagan
Oscar
O
Alcazar
Yogen
Y
Saunthararajah
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology
D000964:Antimetabolites, Antineoplastic; C423449:CpG ODN 1826; D016207:Cytokines; D007376:Interleukin-2; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D000077209:Decitabine; D001374:Azacitidine