Although tumor-specific immune cells are found in stage IV breast cancer patients, they are not able to control tumor growth. This is in part due to tumor stroma that tightly surrounds tumor nests. Tumor stroma contributes to immune evasion of breast cancer in at least two critical ways;by creating a physical barrier that prevents direct contact between tumor infiltrating immune cells and malignant cells, and by producing immunosuppressive cytokines that directly block activation of immune cells and/or attract/activate immuno-suppressive cells such as regulatory T-cells. In this proposal, we will test a new stem cell gene therapy approach that targets tumor stroma cells with the goal to enable existing immune cells to control tumor growth. The specific tumor microenvironment as well as cytokines/growth factors produced by tumor cells trigger differentiation of tumor-infiltrating hematopoietic tumor cells into a unique type of macrophages (so called tumor-associated macrophages -""""""""TAMs""""""""), with a gene expression signature that is distinct from that of tissue macrophages and myeloid cells. TAMs are the prevalent stroma cell type and the number of TAMs directly correlates with breast cancer malignancy. Our central hypotheses are that i) bone marrow derived TAM progenitors can be used to deliver therapeutic transgenes to the tumor stroma, ii) the unique mRNA and microRNA expression profile of TAMs can be used to construct TAM-specific transgene expression systems, and iii) that drug controlled, transgene mediated killing of stroma cells and/or degradation of stroma protein enable long-term control of cancer. We provide a series of preliminary data that support the feasibility of our strategy. We will test our hypotheses in a mouse model of breast cancer involving rat neu-transgenic mice (neu-tg) and syngeneic mammary carcinoma cells (MMC). Key findings will be validated in a second breast cancer model that involves 4T1 cells and BALB/c mice.
Among the tumor stoma cells, tumor-associated macrophages (TAMs) are the prevalent cell type and the number of TAMs directly correlates with breast cancer malignancy. TAMs are a macrophage population that is phenotypically different from other tissue macrophages and bone marrow cells. Our central hypothesis is that bone marrow derived TAM progenitors can be used to deliver therapeutic transgenes to the tumor stroma. Specifically, in a mouse model of breast cancer, we plan to genetically modify, ex vivo, bone marrow stem cells and transplant them into conditioned recipients where they engraft and provide a continuous source of TAM progenitor cells, thereby enabling long-term control of cancer. In this proposal we will focus on transgenes that eliminate obstacles to naturally existing anti-tumor immune cells, created by tumor stroma.
|Richter, Maximilian; Stone, Daniel; Miao, Carol et al. (2017) In Vivo Hematopoietic Stem Cell Transduction. Hematol Oncol Clin North Am 31:771-785|
|Saydaminova, Kamola; Ye, Xun; Wang, Hongjie et al. (2015) Efficient genome editing in hematopoietic stem cells with helper-dependent Ad5/35 vectors expressing site-specific endonucleases under microRNA regulation. Mol Ther Methods Clin Dev 1:14057|
|van Rensburg, R; Beyer, I; Yao, X-Y et al. (2013) Chromatin structure of two genomic sites for targeted transgene integration in induced pluripotent stem cells and hematopoietic stem cells. Gene Ther 20:201-14|
|Beyer, Ines; Cao, Hua; Persson, Jonas et al. (2012) Coadministration of epithelial junction opener JO-1 improves the efficacy and safety of chemotherapeutic drugs. Clin Cancer Res 18:3340-51|
|Strauss, Robert; Hamerlik, Petra; Lieber, André et al. (2012) Regulation of stem cell plasticity: mechanisms and relevance to tissue biology and cancer. Mol Ther 20:887-97|
|Strauss, Robert; Li, Zong-Yi; Liu, Ying et al. (2011) Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. PLoS One 6:e16186|
|Wang, Hongjie; Li, Zong-Yi; Liu, Ying et al. (2011) Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14. Nat Med 17:96-104|
|Beyer, Ines; van Rensburg, Ruan; Strauss, Robert et al. (2011) Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer. Cancer Res 71:7080-90|