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. ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZRG1-IMM-G (02))
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Mohla, Suresh
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University of Chicago
Schools of Medicine
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Gajewski, Thomas F (2015) The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment. Semin Oncol 42:663-71
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Driessens, Gregory; Kline, Justin; Gajewski, Thomas F (2009) Costimulatory and coinhibitory receptors in anti-tumor immunity. Immunol Rev 229:126-44

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