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.
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.
|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|
|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|
|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|
|Chung, David J; Rossi, Marco; Romano, Emanuela et al. (2009) Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood 114:555-63|
|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|
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