Abstract 1347: Immune escape mediator IDO is a crucial defining element of ‘cancer-associated’ inflammation in the tumor microenvironment

Abstract

Abstract Chronic inflammation promotes cancer susceptibility and progression but a precise genetic definition of ‘cancer-associated’ inflammation’ has been elusive. We report that dysregulation of the immune escape mediator indoleamine 2,3-dioxygenase (IDO) is selectively required for carcinogenesis driven by chronic inflammatory stimuli, but not tumor formation per se, thereby linking IDO relatively more tightly to chronic inflammatory disease. IDO is a tryptophan catabolic enzyme that mediates immune tolerance in physiological processes such as pregnancy and pathophysiological processes such as cancer. Here our findings define IDO as a component of the peculiar inflammatory state that contributes to a supportive tumor microenvironment. In the well-established two-stage model of inflammatory skin carcinogenesis, initiated by ras-activating carcinogen DMBA and promoted by pro-inflammatory phorbol ester TPA, we found that genetic deletion of IDO abolished papilloma formation and progression to carcinoma. IDO deletion did not alter the histological phenotype elicited by TPA in skin, but it did abolish generation of a class of IDO+ regulatory antigen-presenting cells within skin-draining lymph nodes as previously reported (1). Intriguingly, carcinogenesis studies conducted in bone marrow chimeras in wild-type or IDO null animals argued that the supportive action of IDO was required mainly in non-immune host cells. In stark contrast to these findings, IDO deletion had no discernable effect on the efficiency of complete skin carcinogenesis (chronic DMBA treatment alone), or on induction and progression of breast carcinomas that were initiated by i.p. DMBA treatment and promoted by progesterone delivery. Thus, IDO contributed to carcinogenesis chiefly through its ability to support a peculiar inflammatory state engendered by TPA that is associated with tumor formation and progression. Two other lines of evidence furthered these findings. First, mice that were deficient in the IDO regulatory tumor suppressor gene Bin1 exhibited a greater susceptibility to two-stage inflammatory skin carcinogenesis, as expected, and the benefits of Bin1 loss to tumor formation relied on IDO dysregulation, based on their reversal by IDO inhibition. Second, we determined that ethyl pyruvate, a simple anti-inflammatory agent known to dampen ‘danger signaling’ and sepsis-like conditions in inflammed tissues, could mediate profound antitumor effects that relied upon an inhibition of IDO expression. Together, our results offered multiple lines of genetic and pharmacological evidence that IDO function is integral to establishing the peculiar inflammatory state that drives cancer, and that genetic pathways of immune escape and ‘cancer-associated’ inflammation may closely overlap. (1) Muller et al. PNAS 105, 17073 (2008). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1347.