Recent observations have indicated that features of the melanoma tumor microenvironment likely determine whether tumor regression versus resistance occurs in response to a successfully generated anti-tumor T cell response. Our preliminary gene expression profiling data on the melanoma tumor microenvironment from patients with advanced disease have suggested two categories of downstream defects: failure to recruit activated T cells into metastatic sites, and presence of immunosuppressive mechanisms in the microenvironment of tumors that have indeed recruited T cells. T cell trafficking has been associated with expression of specific chemokines within tumor sites. Identified immune resistance mechanisms include expression of the inhibitory ligand PD-L1 on the tumor cells themselves, the presence of FoxP3+ regulatory T cells, the tryptophan-catabolizing enzyme IDO expressed by dendritic-like cells and endothelial cells, and the anergy-promoting conditions of having poor B7 expression by APC populations. An additional observation has linked high levels of Notch signaling in melanoma tumors with resistance to immunotherapy and poor T cell recruitement, thus offering a potential link between tumor cell biology and establishment of features of the surrounding microenvironment. These observations have crystalized into the following Specific Aims: 1. To examine the relative contribution of PD-1, regulatory T cells, IDO, and anergy in limiting immune-mediated tumor regression in a mouse preclinical model: 2. To identify cell types producing specific chemokines in the tumor microenvironment and determine the role of selected chemokines in T cell recruitment; and 3. To investigate the role of Notch signaling in melanoma tumor cells in establishing the tumor microenvironment and mediating resistance to T cell-mediated killing. The ultimate goal of this work is to develop strategies to facilitate the effector phase of the anti-tumor immune response by overcoming limitations within the melanoma tumor microenvironment, thus identifying approaches with potential for future clinical application. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127475-02
Application #
7384395
Study Section
Special Emphasis Panel (ZRG1-IMM-G (02))
Program Officer
Mohla, Suresh
Project Start
2007-04-01
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
2
Fiscal Year
2008
Total Cost
$291,650
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Gajewski, Thomas F (2015) The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment. Semin Oncol 42:663-71
Mikucki, M E; Fisher, D T; Matsuzaki, J et al. (2015) Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun 6:7458
Barnes, Sarah E; Wang, Ying; Chen, Luqiu et al. (2015) T cell-NF-?B activation is required for tumor control in vivo. J Immunother Cancer 3:1
Gajewski, Thomas F; Woo, Seng-Ryong; Zha, Yuanyuan et al. (2013) Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr Opin Immunol 25:268-76
Spranger, Stefani; Spaapen, Robbert M; Zha, Yuanyuan et al. (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5:200ra116
Gajewski, Thomas F; Schreiber, Hans; Fu, Yang-Xin (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014-22
Gajewski, Thomas F (2012) Cancer immunotherapy. Mol Oncol 6:242-50
Gajewski, Thomas F; Fuertes, Mercedes; Spaapen, Robbert et al. (2011) Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment. Curr Opin Immunol 23:286-92
Gajewski, Thomas F (2011) Molecular profiling of melanoma and the evolution of patient-specific therapy. Semin Oncol 38:236-42
Zhang, Long; Gajewski, Thomas F; Kline, Justin (2009) PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood 114:1545-52

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