Reinstalling antitumor immunity by inhibiting tumor-derived immunosuppressive molecule IDO through RNA interference.
Tumor-derived immune suppression is a major impediment to successful immune/gene cancer therapy. In the present study, we describe a novel strategy to disrupt tumor-derived immune suppression by silencing a tolerogenic molecule of tumor origin, IDO, using small interfering RNA (siRNA). Silencing of IDO in B16F10 cells in vitro using IDO-siRNA prevented catabolism of tryptophan and inhibited apoptosis of T cells. IDO-siRNA treatment of B16F10 cells in vitro inhibited subsequent growth, tumor formation, and the size of tumor formed, by those cells when transplanted into host mice. In vivo treatment of B16F10 tumor-bearing mice successfully postponed tumor formation time and significantly decreased tumor size. Furthermore, in vivo IDO-siRNA treatment resulted in recovery of T cells responses and enhancement of tumor-specific killing. Thus, silencing IDO may break tumor-derived immune suppression. These data indicate that RNA interference has potential to enhance cancer therapy by reinstalling anticancer immunity.
Zheng
Xiufen
X
Department of Surgery, Pathology, Oncology, Microbiology, and Immunology, London Health Science Centre, London, Ontario, Canada.
Koropatnick
James
J
Li
Mu
M
Zhang
Xusheng
X
Ling
Fengjun
F
Ren
Xiubao
X
Hao
Xishan
X
Sun
Hongtao
H
Vladau
Costin
C
Franek
Jacob A
JA
Feng
Biao
B
Urquhart
Bradley L
BL
Zhong
Robert
R
Freeman
David J
DJ
Garcia
Bertha
B
Min
Wei-Ping
WP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000188:drug therapy; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014364:Tryptophan / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D034741:RNA, Small Interfering; D014364:Tryptophan