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Immune escape as a fundamental trait of cancer: focus on IDO

Abstract

Immune escape is a critical gateway to malignancy. The emergence of this fundamental trait of cancer represents the defeat of immune surveillance, a potent, multi-armed and essential mode of cancer suppression that may influence the ultimate clinical impact of an early stage tumor. Indeed, immune escape may be a central modifier of clinical outcomes, by affecting tumor dormancy versus progression, licensing invasion and metastasis and impacting therapeutic response. Although relatively little studied until recently, immune suppression and escape in tumors are now hot areas with clinical translation of several new therapeutic agents already under way. The interconnections between signaling pathways that control immune escape and those that control proliferation, senescence, apoptosis, metabolic alterations, angiogenesis, invasion and metastasis remain virtually unexplored, offering rich new areas for investigation. Here, an overview of this area is provided with a focus on the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) and its recently discovered relative IDO2 that are implicated in suppressing T-cell immunity in normal and pathological settings including cancer. Emerging evidence suggests that during cancer progression activation of the IDO pathway might act as a preferred nodal modifier pathway for immune escape, for example analogous to the PI3K pathway for survival or the VEGF pathway for angiogenesis. Small molecule inhibitors of IDO and IDO2 heighten chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion and an initial lead compound entered phase I clinical trials in late 2007. New modalities in this area offer promising ways to broaden the combinatorial attack on advanced cancers, where immune escape mechanisms likely provide pivotal support.

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Acknowledgements

I thank my colleagues and collaborators Alexander Muller, Lisa Laury-Kleintop and Laura Mandik-Nayak (Lankenau Institute for Medical Research (LIMR)); Richard Metz (LIMR Development Inc. (LDI)); David Munn and Andrew Mellor (Medical College of Georgia); and Charles Link, Mario Mautino and Nick Vahanian (New Link Genetics Corporation) for productive ongoing discussions of IDO and immune pathobiology in cancer and other settings. I acknowledge Richard Metz for contributing founding ideas about the function of IDO2 as discussed in our earlier publication and elaborated further in the model in Figure 5. My laboratory is supported by the National Cancer Institute R01 Grants CA82222, CA100123, CA109542 and by funds provided by the Lankenau Hospital Foundation. I declare competing interests as a consultant and major shareholder for New Link Genetics Corporation, which supports IDO and IDO2 research in my laboratory and is developing IDO and IDO2 related technology for the therapy of cancer and other chronic diseases associated with pathological immune suppression.

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Prendergast, G. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 27, 3889–3900 (2008). https://doi.org/10.1038/onc.2008.35

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Keywords

  • immunosuppression
  • immunotherapy
  • indoleamine 2,3-dioxygenase
  • Bin1
  • IDO2

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