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Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy

Abstract

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-κB-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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Figure 1: Bin1 loss promotes tumor formation by facilitating immune escape.
Figure 2: Bin1 loss potentiates the NF-κB- and STAT-dependent expression of Indo.
Figure 3: IDO inhibition counteracts the benefit of Bin1 loss to tumor formation.
Figure 4: IDO inhibition cooperates with paclitaxel to cause regression of autochthonous MMTV-Neu breast tumors.
Figure 5: MTH-trp is a potent bioactive inhibitor of IDO.
Figure 6: MTH-trp enhances paclitaxel efficacy.

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Acknowledgements

We thank J. Baker for providing assistance in generating primary keratinocytes from late-stage embyros and for characterizing transgene expression in transformed cell populations. This work was made possible by support from the Lankenau Hospital Foundation, by grants to A.J. Muller from the Sharpe Foundation of the Bryn Mawr Hospital and the State of Pennsylvania Department of Health (CURE/Tobacco Settlement Award), and by grants to G.C. Prendergast from the Department of Defense Breast Cancer Research Program (BC021133), the State of Pennsylvania Department of Health (CURE/Tobacco Settlement Award), and the Charlotte Geyer Foundation.

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Correspondence to George C Prendergast.

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Competing interests

George C. Prendergast is co-founder, president and chief scientific officer and significant stockholder in OncoRx, Inc., a start-up biotechnology company that aims to develop the therapeutic principle described in the manuscript. Alexander J. Muller is scientific co-founder and major stockholder in OncoRX, Inc; James B. DuHadaway is a stockholder in OncoRx, Inc. Prendergast, Muller, and DuHadaway are co-inventors on two published patents incorporating discoveries described in the manuscript: WO 2004 093871 'Novel methods for the treatment of cancer' (pending) and WO 2004 094409 'Novel IDO inhibitors and methods of use' (pending).

Supplementary information

Supplementary Fig. 1

Validation that 1MT administered by time-release pellets achieves sufficient systemic exposure to promote immune rejection of allogeneic concept. (PDF 138 kb)

Supplementary Fig. 2

Attenuation of Bin1 expression during the development of MMTV-Neu mammary tumors. (PDF 165 kb)

Supplementary Fig. 3

Immune competence is required for cooperativity of 1MT with paclitaxel. (PDF 74 kb)

Supplementary Fig. 4

Pharmacokinetic analysis of IDO inhibitors in mouse serum. (PDF 58 kb)

Supplementary Methods (PDF 69 kb)

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Muller, A., DuHadaway, J., Donover, P. et al. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11, 312–319 (2005). https://doi.org/10.1038/nm1196

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