Nature Medicine11, 312 - 319 (2005)
Published online: 13 February 2005; | doi:10.1038/nm1196
Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy
Alexander J Muller1, James B DuHadaway1, P Scott Donover1, Erika Sutanto-Ward1
& George C Prendergast1, 2
1
Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, Pennsylvania 19096 USA.
2
Department of Pathology, Anatomy & Cell Biology, Jefferson Medical College, Thomas Jefferson University, 1020 Walnut Street, Philadelphia, Pennsylvania 19107 USA.
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-B-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.
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B-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.
