T Cell Function and Tumor Metabolism: Effects on Treatment Efficacy and Pre-Treatment Diagnostics

With our understanding of the cellular processes that control cell survival and growth, drug development has accelerated. Cell based therapies such as adoptive cell transfer (ACT) immunotherapy harness the power of tumor specific T cells which are capable of locating and destroying cancer cells. These methods, in contrast to traditional chemotherapy, require the presence of active, functional cells, creating unique challenges. On the other hand, chemotherapeutic agents target specific pathways present in tumor cells; their success often depends on the presence of key enzymes and proteins for proper uptake or activation. Cellular metabolic pathways such as glycolysis and DNA biosynthesis, often upregulated or modified in tumor cells, can exert profound effects on the efficacy of both cell based and chemotherapeutic therapies. In order to further identify key determinants of treatment efficacy, we addressed two distinct areas; (i) T cell function in ACT and factors that modulate the tumor microenvironment, and (ii) noninvasive PET imaging for detecting disease and predicting treatment outcomes. In our ACT and metabolism studies, we demonstrated that pH sensing in CD8+ T cells is important for optimal anti-tumor immunity. While low pH is considered detrimental to T cell function, our results suggest that T cells respond to this signal with increased proliferation in vivo. These results prompted us to explore key determinants of tumor glycolytic metabolism which may modulate the acidic tumor microenvironment. In our PET imaging studies, we investigated the utility of a novel PET imaging probe, [18F]-1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine (FAC), which provides a readout of the deoxycytidine mediated salvage pathway for DNA biosynthesis. We found that FAC PET could predict treatment responses to dFdC, a commonly used nucleoside analog. We extended its application to a murine model of heart transplant, in which we were able to detect reactive lymphocytes which had infiltrated into the rejecting transplant. In summary, the work presented here addresses therapeutic and diagnostic efficacy from a cellular and imaging standpoint, using clinically relevant treatment models and tools to answer our questions.