The immune system is a powerful untapped resource for fighting tumors. Cytotoxic T cells can distinguish tumor cells from normal tissue with pinpoint precision, and they can locate and destroy tumor cells wherever they arise. Immune regulatory mechanisms impinge upon this idealized picture: tumors are notoriously adept at evading or usurping the endogenous anti-tumor immune response. Still, therapeutic interventions can reverse regulatory suppression, and so halt tumor progression or elicit regression. My long term goal is to understand the complex network of cellular interactions that shape the tumor microenvironment, and to develop novel therapeutics aimed at manipulating these dynamics. CD8 T cells do not occur in isolation; they operate in oligoclonal fashion amid regulatory T cells, myeloid cells and other immune infiltrates, not to mention heterogeneous tumor cells, stroma and vasculature. These interactions cannot be accurately modeled using xenografts, nor are they fully replicated in humanized mice that develop human leukocytes, but still face cross-species barriers with respect to immune-stromal interactions and T cell development. My lab clones mice from a variety of tumor-infiltrating lymphocytes in order to study the effects of each lymphocyte type in isolation, and more importantly, when combined with each other and with various immune-based therapies. We also use the technology in reverse to clone mice from tumor-infiltrating Tregs as a means of determining their antigen-specificity, with the ultimate goal of developing small molecule inhibitors for decreasing Treg accumulation in tumors.