Successful immunotherapy ultimately depends on the ability of immune effector cells to migrate to tumor tissues. This process is compromised in tumor microenvironments by limited expression of the molecular array of adhesion molecules and chemokines that function as gatekeepers controlling lymphocyte extravasation across the vascular endothelial barrier. This proposal addresses the central hypothesis that fever-range thermal stimulation, in combination with local delivery of chemokines, can promote efficient recruitment of immune effector cells to tumor tissues. These studies are formulated on the basis of new information that fever-range thermal stress and chemokines act through cooperative mechanisms to promote lymphocyte adhesion to vascular endothelial cell targets. Three independent but complementary approaches are proposed to address our hypothesis: (1) Strategies are proposed to examine the combined effects of fever-range whole body hyperthermia treatment of tumor bearing mice (pancreatic tumors of RIP-Tag5 transgenics and colon 26 syngeneic tumors) with chemokine delivery approaches in order to determine if improved lymphocyte recruitment can be initiated. Regional chemokine presentation by tumor microvessels will be induced either by local delivery of lymphotactic chemokine proteins (i.e., SLC, MIG) or activation of chemokine biosynthesis by IFN-gamma-dependent cytokine cascades. (2) Based on our studies implicating IL-6 as a central mediator of thermal adhesion in lymphocytes, studies are designed to investigate the proadhesive activity of IL- 6/soluble IL-6 receptor complexes and other proinflammatory cytokines (TNF-alpha, IL-1beta, and IFN-gamma) in intratumora/microvesse/s using neutralizing antibodies and cytokine-deficient mice. (3) The molecular mechanisms underlying lymphocyte-endothelial adhesion responses to fever-range thermal stress will be elucidated using combined biochemical, molecular, and pharmacologic approaches. These studies focus on the contributions of IL-6-dependent ERK1/2 MAPK and STAT3 signal transduction pathways in vitro and in vivo. The proposed studies are expected to provide a framework for future evaluation of the efficacy of combined fever-range thermal stress and chemokine delivery as adjuvant therapies in the treatment of cancer.
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