Abstract

Many tumors are potentially immunogenic, as corroborated by documented in vivo tumor-specific immune responses. Spontaneous clearance of established tumors by endogenous immune mechanisms is rare. Tumor immunotherapy generally mediates poor clinical efficiency. The increasing evidence documented fact that the interaction between tumors and host immune system fosters an immunosuppressive network in the tumor environment. Regulatory T cells (Tregs) actively temper tumor specific immunity and are a significant component of this immunosuppressive network. We studied tumor environmental cells in malignant ascites, tumor and draining lymph nodes of patients with ovarian carcinomas. We demonstrate that in humans with ovarian carcinomas a large amount of tumor environmental CD4+ cells were CD4+CD25+FOXP3+ T cells (CD4+ Tregs). We also demonstrate a suppressive CCR7+CD8+IL-10+ T cell population in ovarian tumor draining lymph nodes and malignant ascites. These T cells are previously-unidentified tumor CD8+ Tregs based on conventional definitions. The origin and functional characteristics of these tumor Tregs are poorly understood. Our central hypothesis is that the pathogenic communication between tumors and hosts contributes to induction, and immune modulation of Tregs, and dysfunctional tumor associated dendritic cell signals contribute to the induction of both types of Tregs. B7-H1 is a novel B7 family member implicated in anergy and tolerance. Ovarian tumors trigger B7-H1 expression on normal peripheral DC and enable DC to induce suppressive T cells in vitro. Thus, we will study how and why tumors condition Treg-inducing DC through distinct mechanisms.
Our specific aims are: 1. Test the hypothesis that tumor contributes to Treg induction. 2. Test the hypothesis that tumor-associated DC induce Tregs. 3. Test the hypothesis that tumor-associated DC induced Tregs are detrimental to tumor immunity. 4. Test the hypothesis that B7 family members are critical for Treg induction. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA099985-03
Application #
7448470
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Howcroft, Thomas K
Project Start
2006-09-20
Project End
2010-03-31
Budget Start
2008-08-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$209,581
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Crespo, Joel; Wu, Ke; Li, Wei et al. (2018) Human Naive T Cells Express Functional CXCL8 and Promote Tumorigenesis. J Immunol 201:814-820
Nagarsheth, Nisha; Wicha, Max S; Zou, Weiping (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17:559-572
Maj, Tomasz; Wang, Wei; Crespo, Joel et al. (2017) Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 18:1332-1341
Wang, Weimin; Kryczek, Ilona; Dostál, Lubomír et al. (2016) Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer. Cell 165:1092-1105
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
Peng, Dongjun; Tanikawa, Takashi; Li, Wei et al. (2016) Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling. Cancer Res 76:3156-65
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
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
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 40:772-784

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