Enhancement of dendritic cell-tumor fusion vaccine potency by indoleamine-pyrrole 2,3-dioxygenase inhibitor, 1-MT.
OBJECTIVE
Dendritic cell (DC)-based cancer vaccines are currently being evaluated as novel anti-tumor vaccination strategies, but in some cases, they are demonstrated to have poor clinical efficacies than anticipated. A potential reason is immune tolerance due to the immunosuppressive enzyme, indoleamine-pyrrole 2,3-dioxygenase (IDO). The aim of this study was to determine whether blocking the activity of IDO might improve the anti-tumor efficacy of DC/Lewis lung carcinoma (LLC) fusion vaccine applied to the mouse LLC model.


METHODS
To prepare the DC/LLC fusion vaccine, DCs were fused with LLC using polyethylene glycol (PEG) as described. The IDO expression in the DC/LLC fusion vaccine and in the vaccinated mice was detected by western blot (WB) and/or immunohistochemical (IHC) analysis. This fusion vaccine, as a single agent or in combination with 1-methyl-tryptophan (1-MT, an IDO inhibitor), was administered to LLC mice. The anti-tumor efficacy in different treatment was determined by regular observation of tumor development and the level of splenic cytotoxic T lymphocyte (CTL) response, which was examined by lactate dehydrogenase (LDH) release.


RESULTS
In the LLC mice, we observed that IDO-positive cells were extensively accumulated in tumor draining lymph nodes (TDLNs). Furthermore, WB and IHC analysis results showed that vaccination with fusion DC/LLC cells alone caused significant up-regulation of IDO in spleens. 1-MT enhanced the anti-tumor efficacy elicited by DC/LLC fusion vaccine via delaying the tumor development and inducing stronger splenic CTL responses.


CONCLUSIONS
Our results indicate an IDO-mediated immunosuppressive mechanism might be involved in weakening the anti-tumor efficacy elicited by DC/LLC fusion vaccine, and specific inhibition of IDO activity might be required for development of cancer vaccines.
Ou
Xueling
X
Center of Microbiology, Biochemistry, and Pharmacology, School of Pharmaceutical Science, Sun Yat-Sen University, 74 Zhongshan Road, Guangzhou 510080, China.
Cai
Shaohui
S
Liu
Peng
P
Zeng
Jun
J
He
Yuwen
Y
Wu
Xinyao
X
Du
Jun
J
D000818:Animals; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology*; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000628:therapy*; D003713:Dendritic Cells / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D007108:Immune Tolerance / Q000502:physiology; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008198:Lymph Nodes / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
D019496:Cancer Vaccines; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan