Role of Proinflammatory Cytokines in Thermal Activation of Lymphocyte Recruitment in Breast Tumor Microvessels
Annual summary rept. 23 Feb 2004-22 Feb 2005
ROSWELL PARK CANCER INST BUFFALO NY
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A major challenge is to develop approaches to target delivery of tumor-specific immune effector cells to tumor tissues. Immune cells are frequently excluded from the intratumoral region of primary tumors including breast cancer. Thus, these cells cannot initiate contact-dependent lysis of tumor targets. We have reported that poor infiltration of tumor tissues in murine models correlates with limited expression of critical gatekeeper adhesion molecules e.g., intercellular adhesion molecule-1, ICAM-1 which control egress of blood-borne lymphocytes into tissues. Our studies demonstrate that fever-range thermal therapy upregulates ICAM-1 expression on intratumoral vessels in transplantable murine breast tumors and other tumor models. ICAM-1 upregulation occurs principally on CD31 vessels of tumor and lymphoid tissues, but not in extralymphoid organs. Thermal induction of ICAM-1 correlates with enhanced CD8 T cell adhesion, homing and infiltration in tumor tissues. Neutralization of selected inflammatory cytokines IL-6, but not TNF-alpha or IL-1beta suppresses thermal induction of ICAM-1 on vessels. Soluble gp130 also prevented ICAM-1 induction, indicating that thermal activities in vascular targets are dependent on an IL-6 trans-signaling mechanism. These results support the hypothesis that IL-6 dependent signaling mechanisms overcome the microvascular barrier to tumor immunity through stimulation of heightened trafficking of lymphocyte subsets to tumor sites.
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- Medicine and Medical Research