Project 3T cells, which normally function to monitor for aberrantly expressed intracellular antigens, are deleted duringdevelopment if they are autoreactive. Many tumorigenic mutations result in only minor deviations from self inthe epitopes presented to T cells by products of the major histocompatibility complex (MHC). Hence, the Tcell repertoire that remains after thymic development and selection consists largely of low-affinity receptorsagainst potential tumor antigens. To overcome this deficiency in the tumor-specific T cell repertoire, variouslabs have attempted to transfer genes that encode a tumor-specific a(3 T cell receptor into a patient's T cellsex vivo. In concert with these efforts, TCRs have been engineered for higher affinities against peptide/MHCantigens. Our principle hypothesis is that these high-affinity TCRs can be used to treat cancer, either inadoptive T cell therapies or as soluble targeting molecules (by analogy to monoclonal antibodies). Whilethese approaches show promise, significant questions remain regarding their optimal use. The purpose ofthis project is to address these questions, and thereby to interface with other projects in this program that willdirectly apply the findings to several different tumor models. The project will make use of our extensiveearlier studies in the mouse system involving CTL clone 2C, and a collection of 2C TCR mutants that havealready been engineered with a range of affinities.
The specific aims of the project that will be directed byDavid Kranz at the University of Illinois are:
Specific Aim 1. To examine the binding properties of TCR 2Cthat result in optimal specificity, peripheral expansion, survival, and activity of transduced T cells.
SpecificAim 2. To explore various strategies to increase the surface levels of exognous TCRs introduced by genetransduction.
| Arina, Ainhoa; Karrison, Theodore; Galka, Eva et al. (2017) Transfer of Allogeneic CD4+ T Cells Rescues CD8+ T Cells in Anti-PD-L1-Resistant Tumors Leading to Tumor Eradication. Cancer Immunol Res 5:127-136 |
| Kammertoens, Thomas; Friese, Christian; Arina, Ainhoa et al. (2017) Tumour ischaemia by interferon-? resembles physiological blood vessel regression. Nature 545:98-102 |
| Tang, Haidong; Zhu, Mingzhao; Qiao, Jian et al. (2017) Lymphotoxin signalling in tertiary lymphoid structures and immunotherapy. Cell Mol Immunol 14:809-818 |
| 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 |
| 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 |
| 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 |
| Spaapen, Robbert M; Leung, Michael Y K; Fuertes, Mercedes B et al. (2014) Therapeutic activity of high-dose intratumoral IFN-? 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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