CD8+ T cells can destroy established solid tumors, but relapse is common. Two major rate limiting steps are: lack of proper priming or block in the effector phase. This program focusses on solid tumors that represent the majority of human cancers. Local barriers imposed by the solid tumor microenvironment not only impede radiation and chemotherapy but also CD8+ T cell-mediated tumor destruction. This makes cancer recurrence after these therapies a common problem. Clinical cancers usually harbor at least 10A9 cancer cells containing a variable number of cancer stem cells. These cancer cells are genetically diverse, and the expectation that any single therapy or mechanism will eradicate the entire population of cancer cells seems unrealistic. Therefore, this proposal is not only to induce, restore and improve destructive power of CD8+ T cells, but to find strategies for enlisting additional mechanisms and treatments in a predictably synergistic way. Project 1 will study the factors that will mediate and define innate factors that can lead to successful T cell priming in response to a growing tumor with particular emphasis on type I interferons and downstream factors like IL-1 leading to cross-priming of CD8+ T cells. Project 2 will target mice with established solid tumors, distant metastases and determine whether intratumoral LIGHT treatment in conjunction with anti-Her2/neu antibody can increase tumor cell apoptosis and thereby increase CD8+ T cell priming and alter the tumor microenvironment to allow T cell maturation to a full effector stage. Project 3 will study the requirements and possible limitations of using engineered T cell receptors for the destruction of solid tumors. Project 4 will exploit the finding that targeting the stroma of solid tumors CD8+ T cells can prevent escape of cancer variants from therapy. The Protein Expression and Peptide Core will provide the proteins and peptides needed for the above projects, while the Administrative/Statistics/Optical Imaging Core will overlook the projects, give statistical advice and allow optical imaging analysis in real time of the events occurring in the tumor microenvironment following manipulations proposed in the four projects. CD8+ T cells can destroy well-established solid tumors but relapse is very common. The goal is to (i) manipulate and target the tumor microenvironment to overcome recurrence from therapy and (ii) explore novel immunological concepts and engineered reagents that can synergize with other novel as well as conventional therapies.
| 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; 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 |
| 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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