Tumor development elicits responses from both the innate and adaptive arms of the immune system that could be beneficial to eradicate tumors. In turn, progressive tumor growth in humans and laboratory animals is frequently accompanied by a concomitant immunosuppression regardless of tumor location or etiology. The elements responsible for this downregulation of the immune responses are not clearly understood, however, current technology has allowed new insights into the mechanisms underlying these alterations. We propose to continue our studies using our well-characterized murine mammary tumor model to further elucidate the interactions between the growing neoplasms and the immune effector cells. Based on our previous findings we plan: (1) to evaluate the possible contributions of vascular endothelial growth factor (VEGF) and other tumor derived factors as well as the interactions between thymocytes and thymic microenvironment in the thymic involution of mammary tumor bearers; (2) to additionally analyze the mechanisms of disregulation of tumor bearers' macrophage functions and to delineate the effects of tumor development on Toll-like receptor 4 (TLR4) expression and its signaling pathway; (3) to further analyze the molecular bases leading to the overexpression of matrix metalloproteinase-9 (MMP-9) on T cells from tumor bearers and the possible role of this molecule in lymphocyte and tumor cell migration; (4) to extend our investigations into the tumor cell characteristics and immune effector cells involved in the lack of growth of DA-3/sec cells in vivo and the protective effects they confer against the growth of other tumors. An understanding of the cellular and molecular mechanisms responsible for the host-tumor interactions and the tumor-induced immunological alterations will help develop novel immunotherapeutic interventions.
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