Tumors express a range of antigens including self-antigens. CD4+CD25+ regulatory T (Treg) cells are critical for maintaining T cell tolerance to self-antigens. Treg cells are thought to dampen tumor associated antigen (TAA)-specific T cell immunity and to be the main obstacle tempering successful immunotherapy and active vaccination. Therefore, manipulation of regulatory T cells, including depletion, blocking trafficking into tumors, or reducing their differentiation/expansion, survival and suppressive mechanisms represent new strategies for cancer treatment. However, it remains poorly understood how Tregs survive and function in the environment with chronic hypoxia and nutrient depletion, and how the phenotypic and suppressor integrity of Tregs is maintained in the tumor microenvironment enriched with high levels of inflammatory factors. In this proposal, based on our preliminary data, we hypothesize that hypoxia activates the "stemness program" of Treg cells, reshapes local immune profile in the tumor microenvironment and contributes to tumor immune evasion. To test this hypothesis, extensive experiments are proposed herein along with three specific aims:
Aim 1 is to test the hypothesis that hypoxia activates the "stemness program" in human tumor Tregs.
Aim 2 is to test the hypothesis that hypoxia promotes Treg functional stability and integrity in human tumor.
Aim 3 is to test the hypothesis that hypoxia activates key molecular targets in tumor Tregs.
CD4+CD25+ regulatory T (Treg) cells are critical for maintaining T cell tolerance to self-antigens. Treg cells are thought to dampen tumor associated antigen (TAA)-specific T cell immunity and to be the main obstacle tempering successful immunotherapy and active vaccination. Therefore, manipulation of regulatory T cell biology represents new strategies for cancer treatment. In the application we examine the effects of hypoxia on Treg cells in the tumor. We may identify important molecular pathways controlling Treg biology in human tumor. The application may provide insight into new approaches in cancer therapy.
|Zou, Weiping; Wolchok, Jedd D; Chen, Lieping (2016) PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med 8:328rv4|
|Zhao, Ende; Maj, Tomasz; Kryczek, Ilona et al. (2016) Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol 17:95-103|
|Wang, Weimin; Kryczek, Ilona; DostÃ¡l, LubomÃr et al. (2016) Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer. Cell 165:1092-105|
|Nagarsheth, Nisha; Peng, Dongjun; Kryczek, Ilona et al. (2016) PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer. Cancer Res 76:275-82|
|Peng, Dongjun; Kryczek, Ilona; Nagarsheth, Nisha et al. (2015) Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527:249-53|
|Kryczek, Ilona; Lin, Yanwei; Nagarsheth, Nisha et al. (2014) IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 40:772-84|
|Crespo, Joel; Sun, Haoyu; Welling, Theodore H et al. (2013) T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol 25:214-21|
|Cui, Tracy X; Kryczek, Ilona; Zhao, Lili et al. (2013) Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39:611-21|
|Kryczek, Ilona; Liu, Suling; Roh, Michael et al. (2012) Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells. Int J Cancer 130:29-39|
|Zhao, Ende; Xu, Huanbin; Wang, Lin et al. (2012) Bone marrow and the control of immunity. Cell Mol Immunol 9:11-9|
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