Abstract

Tumor microenvironment is comprised of dysfunctional immune cells that have been reprogrammed by active tumor-mediated processes to defeat tumor-specific immunity. Two major mediators of poor tumor immunity are dysfunctional APCs including stromal macrophages (MFs) and regulatory T cells (Tregs). MFs are one of the most important cellular components and APCs in solid human tumor stroma. However, the nature of MFs in HUMAN tumor microenvironment is poorly understood. Our data demonstrate two distinct MF populations in human ovarian cancer: B7-H4+TGF-?high and B7-H4- TGF-?low MFs. We observed that (i) B7-H4+TGF-?high MFs suppress T cell activation and blocking B7-H4 reduced this suppressive activity;(ii) Repetitive stimulation with B7-H4+TGF-?high MFs converted naive T cells into CD4+CD25+ T cells with strong FOXP3 expression;(iii) B7-H4- MFs can be switched into B7-H4+ MFs in response to tumor Tregs. The data lead to our 3 specific aims to test the following hypotheses:
Aim 1. B7-H4+TGF-?high and B7-H4-TGF-?low MFs are distinct macrophage subpopulations Aim 2. B7-H4+TGF-?high MFs induce regulatory T cells through TGF-? and B7-H4 Aim 3. Tumor environmental elements promote MF differentiation toward B7-H4+TGF-phigh macrophages. The proposal mechanistically links several layers of the immunosuppressive networks in the tumor environment including dysfunctional APCs, Tregs and stromal cells, and provide a consensus to explain how the immunosuppressive networks work together in forming tumor immune tolerization in human tumor. Furthermore, in addition to ovarian cancer, we found B7-H4+ MFs in colon cancer and breast cancer. The proposal may demonstrate that induction of B7-H4+TGF-?high MFs is a broad and novel mechanism for carcinomas to escape from cellular immune responses and targeting this specific MF population is a novel strategy for treating human cancers.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA123088-05
Application #
8058630
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Mccarthy, Susan A
Project Start
2007-08-01
Project End
2012-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
5
Fiscal Year
2011
Total Cost
$280,136
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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