Targeting the secretory pathway in cytotoxic T lymphocytes to modulate their cytolytic capacity in cancer immunotherapy

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The estrogen-tunable gene EBAG9 tempers the killing activity of cytotoxic T ymphocytes, implicating that estrogen and its receptor inhibitors could also be intimately linked with T-cell mediated cancer immunosurveillance. Adoptive T cell transfer for the cure of cancer has to implicate strategies to overcome a tolerizing milieu, either by depleting tolerogenic factors, or by ameliorating the capacity of effector T cells. While many experimental and some clinical trials have focused on variables such as a) antigen type and mode of presentation, b) number and activation status of transferred T cells, c) origin of tumor cells, and d) conditioning of the patient, cell biological aspects of the T cell response have received little attention thus far. We will operationally define T cell avidity as a variable that is influenced by synthesis and storage of cytolytic effector molecules, intracellular vesicle transport, and organelle maturation. Specific aims within this proposal are: 1) Enhancement of cytolytic capacity of adoptively transferred T cells, as mediated by pharmacologic estrogen modulation; 2) Generation of highly avid anti tumor T cells through shRNAmediated EBAG9-downregulation; 3) Assessment of the relationship between enhanced cytolytic capacity and CTL memory formation; 4) Quantification of T cell receptor repertoire diversity in relationship to the modulation of lytic granule maturation; 5) Investigations on the link between excessive cytotoxic function and immune homeostasis.