IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells.

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.

• Authors: Daniel T Fisher, Qing Chen, Joseph J Skitzki, Jason B Muhitch, Lei Zhou, Michelle M Appenheimer, Trupti D Vardam, Emily L Weis, Jessica Passanese, Wan-Chao Wang, Sandra O Gollnick, Mark W Dewhirst, Stefan Rose-John, Elizabeth A Repasky, Heinz Baumann, Sharon S Evans
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 121 Issue 10 Pg. 3846-59 (Oct 2011) ISSN: 1558-8238 [Electronic] United States
• PMID: 21926464 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• E-Selectin
• IL6 protein, human
• Interleukin-6
• P-Selectin
• Intercellular Adhesion Molecule-1

Topics

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