This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Manipulation of lymphocyte homeostasis for enhancing anti-tumor immunity: New insights into how the immune system recognizes malignant cells have lead to the development of novel treatments in cancer. One such therapy elicits T lymphocytes capable of destroying cancer cells after recognizing specific tumor antigens.Successful T cell-based immunotherapy is dependent upon the appropriate activation of sufficient numbers of tumor-reactive T cells and the long-term persistence of these T cell responses, which is necessary to prevent tumor recurrences. However, T cell homeostatic mechanisms closely govern the overall size and diversity of the T-cell pool by balancing lymphocyte generation, survival, and death thereby, ensuring a constant number of naive and activated T cells. Unfortunately, cancer vaccines aimed at generating anti-tumor responses generally have failed to cure or control the disease due to 1) sub-optimal T cell activation, in part resulting from low precursor frequencies against tumor antigens and 2) the short-term duration of anti-tumor T cell responses. Our main hypothesis is that these obstacles may be overcome by manipulating some of the immunological mechanisms that help maintain T-cell homeostasis. More specifically, we theorize that by partially depleting the peripheral T cell compartment and allowing this space to be refilled in the presence of protein or peptide antigenic stimulation will skew the development of the T cell repertoire towards a lymphocyte population with long-lived anti-tumor activity. In order to translate these findings for use on cancer patients we have selected various modes to disrupt lymphocyte homeostasis that are clinically relevant and readily available. To explore this hypothesis we propose to study the following specific aims.
Aim 1; To study the effect of disrupting lymphocyte homeostasis on the expansion, function and persistence of vaccine stimulated anti-tumor T lymphocytes.
Aim 2; To assess whether modifying T-cell homeostasis plus peptide/protein vaccines will preferentially augment anti-tumor T cell activity specifically, in the context of pre-existing anti-tumor T cell responses.
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