Observations made studying anti-tumor immune responses in patients with metastatic melanoma have reshaped critical questions to be addressed mechanistically in preclinical models. In many melanoma patients, and in several animal studies, the rate limiting step in the anti-tumor immune response appear to be at the level of immune resistance at the effector phase in the tumor microenvironment. In the previous funding period we have made significant advances in understanding these mechanisms of resistance and how to overcome them. However, this new perspective on anti-tumor immunity has generated a critical new question: if tumor antigen-specific T cells frequently can be productively activated without any external intervention, then which innate immune factors are facilitating proper T cell differentiation, in the absence of an obvious infectious pathogen? In theory this should occur only with difficulty, as there are no exogenous TLR ligands to costimulate antigen-presenting cell (ARC) populations in the context of a growing tumor. Our preliminary data have indicated a role for host type I interferons (IFNs) and also IL-1 in this innate immune """"""""awareness"""""""" that leads to productive tumor antigen cross-presentation to CD8+ T cells in vivo. In the first specific aim of this proposal, we will identify and characterize the ARC populations mediating apontaneous cross-priming of tumor antigen-specific CD8+ T cells in vivo. The rationale is that we need to understand what occurs normally in order to determine where the blocks are in this process in specific mutant mice. In the second specific aim, we will determine the mechanism by which host type I IFNs facilitate tumor antigen cross-presentation in vivo. In the third specific aim, we will elucidate the role of host IL-1 and its relationship to type I IFNs in productive cross-priming in vivo. These studies will take advantage of several unique reagents and model systems, including a TCR tetramer to recognize peptide/class complexes, conditional IFN-a/bR knockout mice, and a genetic tumor model encoding a model tumor antigen. Understanding the factors and processes that mediate successful T cell priming to tumor antigens when it does occur should point toward new strategies to induce better cross-priming when it does not occur spontaneously.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA097296-10
Application #
8375075
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$269,433
Indirect Cost
$60,701
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Arina, Ainhoa; Idel, Christian; Hyjek, Elizabeth M et al. (2016) Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc Natl Acad Sci U S A 113:7551-6
Smith, Sheena N; Harris, Daniel T; Kranz, David M (2015) T Cell Receptor Engineering and Analysis Using the Yeast Display Platform. Methods Mol Biol 1319:95-141
Corrales, Leticia; Glickman, Laura Hix; McWhirter, Sarah M et al. (2015) Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep 11:1018-30
Gajewski, Thomas F; Corrales, Leticia (2015) New perspectives on type I IFNs in cancer. Cytokine Growth Factor Rev 26:175-8
Blankenstein, Thomas; Leisegang, Matthias; Uckert, Wolfgang et al. (2015) Targeting cancer-specific mutations by T cell receptor gene therapy. Curr Opin Immunol 33:112-9
Binder, David C; Schreiber, Hans (2014) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors--letter. Cancer Res 74:632; discussion 635
Deng, Liufu; Liang, Hua; Burnette, Byron et al. (2014) Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 124:687-95
Yang, Xuanming; Zhang, Xunmin; Fu, May Lynne et al. (2014) Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses. Cancer Cell 25:37-48
Spaapen, Robbert M; Leung, Michael Y K; Fuertes, Mercedes B et al. (2014) Therapeutic activity of high-dose intratumoral IFN-β requires direct effect on the tumor vasculature. J Immunol 193:4254-60
Woo, Seng-Ryong; Fuertes, Mercedes B; Corrales, Leticia et al. (2014) STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830-42

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