Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy.
Immune escape is a crucial feature of cancer progression about which little is known. Elevation of the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) in tumor cells can facilitate immune escape. Not known is how IDO becomes elevated or whether IDO inhibitors will be useful for cancer treatment. Here we show that IDO is under genetic control of Bin1, which is attenuated in many human malignancies. Mouse knockout studies indicate that Bin1 loss elevates the STAT1- and NF-kappaB-dependent expression of IDO, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In MMTV-Neu mice, an established breast cancer model, we show that small-molecule inhibitors of IDO cooperate with cytotoxic agents to elicit regression of established tumors refractory to single-agent therapy. Our findings suggest that Bin1 loss promotes immune escape in cancer by deregulating IDO and that IDO inhibitors may improve responses to cancer chemotherapy.
Muller
Alexander J
AJ
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, Pennsylvania 19096, USA.
DuHadaway
James B
JB
Donover
P Scott
PS
Sutanto-Ward
Erika
E
Prendergast
George C
GC
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000502:physiology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D017239:Paclitaxel / Q000627:therapeutic use; D051381:Rats; D050794:STAT1 Transcription Factor; D013867:Thiohydantoins / Q000494:pharmacology / Q000627:therapeutic use; D015534:Trans-Activators / Q000502:physiology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D019139:Tumor Escape / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; C109221:Bin1 protein, mouse; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007211:Indoles; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; C494081:Stat1 protein, rat; D013867:Thiohydantoins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C500233:methyl-thiohydantoin-tryptophan; D007371:Interferon-gamma; D014366:Tryptophan Oxygenase; D017239:Paclitaxel