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Tuesday, December 05, 2006 1:30:27 PM
Scientific Committee on Lymphocyte Biology
The Great Escape: Mechanisms for Evading the Host Anti-Tumor Response
Speakers:
Hyam Levitsky, MD, Johns Hopkins University School of Medicine, Baltimore, MD
Regulatory T Cells as a Barrier to Anti-Tumor Immunity
"Some of the earliest studies of “suppressor T cells” were conducted in the analysis of the host response to cancer, but difficulties in isolating a defined lymphocyte population capable of mediating dominant forms of tolerance led to skepticism about their existence. More recently, cells with this functional capacity have been identified, both as a defined pre-committed lineage emerging from the thymus as well as an acquired state of differentiation following certain forms of T cell activation in the periphery. In the mouse, CD4+ T cells which constitutively express high affinity IL2 receptors, CTLA-4, and the transcriptional repressor, foxp3, have been shown to blunt immune responses against self-antigens and tumor antigens. Such “Tregs” fail to make IL2 and are dependent upon this cytokine produced by the cells they suppress for survival in the periphery, establishing a negative feedback loop that maintains lymphocyte homeostasis. In both mouse and human studies, Tregs have been found to accumulate within tumor tissues, and can effectively blunt effector function of helper CD4+ T cells as well as CD8+ cytotoxic T lymphocytes. Similarly, tumor-antigen specific Tregs block the clonal expansion of effector cells in response to “therapeutic” cancer vaccines, and Tregs may themselves become amplified following such vaccination. Clinical studies in some solid tumors have reported a correlation between high intratumoral Treg densities and an adverse prognosis. Several strategies for Treg depletion have shown synergy when combined with vaccination against established tumors in mouse models, and early phase clinical trials. Current areas of basic investigation are focusing on defining the mechanisms by which Tregs suppress effector cell function, and on what features of the tumor microenvironment support Treg recruitment, differentiation, survival, and expansion. As Tregs also are critical regulators of lymphocyte homeostasis, there is also great interest in the factors that influence their repopulation following chemotherapy-induced lymphopenia. The changing ratio of T effector cells to Tregs during immune reconstitution significantly impacts the ability of tumor vaccines or adoptively transferred tumor-specific T cells to mediate tumor regression, and is a ripe target for therapeutic manipulation."
I believe one may be able to find Cancerfoe and Tantoguy with a google search on their web name....maybe a personal invitation might get them back? Need everyone's brain to even begin to understand this subject! Thanks for your posts and everyone's collective effort here....great thread.
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