Publications [#210163] of Mark W. Dewhirst

Papers Published

1. DT Fisher, Q Chen, JJ Skitzki, JB Muhitch, L Zhou, MM Appenheimer, TD Vardam, EL Weis, J Passanese, WC Wang, SO Gollnick, MW Dewhirst, S Rose-John, EA Repasky, H Baumann, SS Evans, IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells., The Journal of clinical investigation, vol. 121 no. 10 (October, 2011), pp. 3846-59, ISSN 1558-8238 [doi]
   (last updated on 2012/10/26)

   Abstract:
   Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8+ T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5°C ± 0.5°C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8+ effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-α and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor-α fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6-dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6-rich tumor microenvironment can be exploited to create a therapeutic window to boost T cell-mediated antitumor immunity and immunotherapy.

   Keywords:
   Animals • Apoptosis • Cell Line, Tumor • Cell Movement • E-Selectin • Humans • Hyperthermia, Induced • Intercellular Adhesion Molecule-1 • Interleukin-6 • Mice • Microvessels • Models, Immunological • Neoplasms • P-Selectin • Signal Transduction • T-Lymphocytes, Cytotoxic • Tumor Microenvironment • blood supply* • immunology • immunology* • metabolism • metabolism* • pathology • therapy