Hosts with established tumors fail to respond to tumor-associated antigens, and often appear to actively suppress responses to anti-tumor vaccines. This tumor-induced suppression constitutes a fundamental barrier to cancer immunotherapy. During the previous period of support, the project has identified the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) as occupying a pivotal role in coordinating this tumor-induced state of suppression and unresponsiveness. In mouse models, IDO expression directly suppresses CD8+ CTL responses, and potently enhances the suppressive activity of Foxp3+ Tregs. If IDO is inhibited using the IDO-inhibitor drug 1-methyl-tryptophan (1MT), hosts with established tumors become markedly more responsive to anti-tumor vaccines and T cell adoptive transfer. Further, when IDO is blocked, vaccine-induced inflammation becomes able to abrogate Treg-mediated suppression and re-program pre-existing Foxp3+ Tregs into pro-inflammatory T-helper/TH17 cells, resulting in significantly enhanced anti- tumor responses. The proposal will use models of defined TCR-transgenic T cells, therapeutic vaccination of large established tumors, and genetically-defined mouse strains, to test the following hypotheses:
Aim 1 - Test the hypothesis that IDO-activated Tregs in established tumors and in vaccine-draining LNs mediate dominant suppression of vaccine-induced CTL and T-helper responses;but when IDO is blocked, vaccine-induced inflammation drives down-regulation of Treg-mediated suppression, re-programming of Tregs into polyfunctional T-helper cells, and IL-2-mediated enhancement of intratumoral CTL effector function.
Aim 2 - Test the hypothesis that when IDO is blocked, CTLs become able to undergo full effector maturation in the tumor, mediate tumor-cell killing, and drive epitope-spreading to new CTLs against endogenous tumor antigens;but that activated CTL are still subject to PD-1-mediated mechanisms of clonal exhaustion within the tumor, and synergistically benefit from blockade of the PD-1 pathway.
Aim 3 - Test the hypothesis that IDO inhibits CTL homing to the tumor by suppressing upregulation of chemokine receptor CXCR3 on activated CTLs, and by suppressing inflammation-induced VCAM-1 expression on tumor endothelial cells;but that inhibition of IDO allows therapeutic vaccination to create local inflammation within the tumor, driving active recruitment of anti-tumor effector cells. The long-term goal of these studies is to develop clinically-applicable combinations of an IDO-inhibitor drug plus therapeutic anti-tumor vaccines;and to use this combination to abrogate tumor-induced immune suppression and allow effective T cell responses against established tumors. The IDO-inhibitor drug 1-methyl- tryptophan (1MT) is currently entering Phase I clinical trials, so this strategy has high translational potential.

Public Health Relevance

One of the fundamental barriers to successful immunologic therapy of cancer is the fact that tumors create a state of suppression and unresponsiveness to their own antigens. The natural immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) has been discovered to play a pivotal role in helping create this immune suppression. The long-term goal of the proposed studies is to develop treatment strategies based on the newly developed class of IDO-inhibitor drugs, using them in combination with therapeutic anti-tumor vaccines, so as to abrogate tumor-induced immune suppression and allow effective T cell responses against established tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112431-08
Application #
8206622
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2005-01-14
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
8
Fiscal Year
2012
Total Cost
$247,529
Indirect Cost
$79,142
Name
Georgia Regents University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Hong, Yuan; Manoharan, Indumathi; Suryawanshi, Amol et al. (2015) β-catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Res 75:656-65
Hong, Yuan; Peng, Yibing; Guo, Z Sheng et al. (2014) Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology 59:1448-58
Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao et al. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 74:3441-53
Li, Minghui; Bolduc, Aaron R; Hoda, Md Nasrul et al. (2014) The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer 2:21
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
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
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
Zhou, Qing; Munger, Meghan E; Veenstra, Rachelle G et al. (2011) Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117:4501-10
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
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

Showing the most recent 10 out of 19 publications