Tumors create a pathologic state of acquired tolerance toward their own antigens. This represents a fundamental barrier to successful immunotherapy of cancer. The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is an innate molecular mechanism of acquired tolerance in vivo. IDO has been implicated as an important contributing mechanism to tumor-induced tolerance, particularly during the clinically-relevant period when the tumor must re-establish tolerance to itself following chemotherapy. Despite its potential importance, however, the mechanisms by which IDO creates its potent immunoregulatory effects remain incompletely understood at the cellular and molecular level. During the previous period of support, successful studies using genetically-defined murine models have: (i) elucidated the identity of the novel subset of plasmacytoid dendritic cell (pDC) in tumor-draining lymph nodes that express IDO;(ii) identified the downstream molecular pathway in T cells by which IDO exerts key biologic effects, comprising the stress- kinase GCN2 and downstream transcription factor CHOP/gadd153;(iii) reported the novel discovery that IDO- expressing pDCs directly activate mature Foxp3+ regulatory T cells (Tregs) for potent suppressor activity via the GCN2->CHOP pathway;and (iv) shown that, when Tregs are exposed to pro-inflammatory signals from activated effector T cells, IDO and the GCN2->CHOP pathway act to maintain Tregs in their suppressive phenotype;whereas in the absence of IDO, Tregs are converted into a T-helper phenotype indistinguishable from TH17 cells. Based on these novel findings, the current proposal addresses the hypothesis that IDO functions as a key molecular switch for Tregs in tumor-draining LNs, regulating the fundamental choice between inflammation-induced activation of Treg suppressor function, versus inflammation-induced abrogation of the Treg phenotype.
Aim 1 will test the hypothesis that pro-inflammatory signals from activated effector T cells drive Tregs into a forced choice - either to become potently suppressive, or to lose the Treg phenotype and convert to TH17-like cells - and that the outcome of this choice is dictated by IDO-mediated regulation of IL-6 production by pDCs and activation of the GCN2->CHOP pathway in Tregs.
Aim 2 will use genetically- defined mouse models to test the hypothesis that the IDO pathway is critical in regulating the balance between Treg-mediated suppression versus pro-inflammatory TH17/effector T cell activation in tumor-bearing hosts, particularly during the critical window of recovery following chemotherapy.
Aim 3 will use established B16 tumors treated with anti-tumor vaccine plus the IDO-inhibitor drug 1MT to test the hypothesis that blocking IDO allows therapeutic immunization to break tolerance to established tumors;and that the ROR?t-mediated conversion of Tregs to TH17-like cells is mechanistically required in order for this to occur. The long-term translational goal of these studies is to exploit the newly-available IDO-inhibitor drugs, now entering Phase I clinical trials, as a novel and clinically applicable strategy to block Treg activation by tumors.

Public Health Relevance

Tumors actively suppress attempts by the immune system to attack and eliminate them. The current proposal studies a novel and clinically relevant mechanistic link between two powerful immunosuppressive pathways operating in tumor-bearing hosts: the immunoregulatory enzyme IDO (indoleamine 2,3- dioxygenase), and the potently suppressive regulatory T cell (Treg) system. Understanding the molecular mechanisms that link these two pathways has direct implications for the design of better clinical immunotherapy regimens in cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Georgia Regents University
Schools of Medicine
United States
Zip Code
Sharma, Madhav D; Huang, Lei; Choi, Jeong-Hyeon et al. (2013) An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38:998-1012
Divanovic, Senad; Sawtell, Nancy M; Trompette, Aurelien et al. (2012) Opposing biological functions of tryptophan catabolizing enzymes during intracellular infection. J Infect Dis 205:152-61
Ravishankar, Buvana; Liu, Haiyun; Shinde, Rahul et al. (2012) Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A 109:3909-14
Baban, Babak; Chandler, Phillip R; Johnson 3rd, Burles A et al. (2011) Physiologic control of IDO competence in splenic dendritic cells. J Immunol 187:2329-35
Makala, Levi H C; Baban, Babak; Lemos, Henrique et al. (2011) Leishmania major attenuates host immunity by stimulating local indoleamine 2,3-dioxygenase expression. J Infect Dis 203:715-25
Sharma, Madhav D; Hou, De-Yan; Baban, Babak et al. (2010) Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33:942-54
Johnson 3rd, Burles A; Kahler, David J; Baban, Babak et al. (2010) B-lymphoid cells with attributes of dendritic cells regulate T cells via indoleamine 2,3-dioxygenase. Proc Natl Acad Sci U S A 107:10644-8
Jasperson, Lisa K; Bucher, Christoph; Panoskaltsis-Mortari, Angela et al. (2009) Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood 114:5062-70
Baban, Babak; Chandler, Phillip R; Sharma, Madhav D et al. (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183:2475-83
Sharma, Madhav D; Hou, De-Yan; Liu, Yanjun et al. (2009) Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113:6102-11

Showing the most recent 10 out of 23 publications