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

• Published in: The Journal of clinical investigation 2011-10, Vol.121 (10), p.3846-3859
• Main Authors: Fisher, Daniel T, Chen, Qing, Skitzki, Joseph J, Muhitch, Jason B, Zhou, Lei, Appenheimer, Michelle M, Vardam, Trupti D, Weis, Emily L, Passanese, Jessica, Wang, Wan-Chao, Gollnick, Sandra O, Dewhirst, Mark W, Rose-John, Stefan, Repasky, Elizabeth A, Baumann, Heinz, Evans, Sharon S
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomedical research; Blood vessels; Cancer; Cell division; Cell Line, Tumor; Cell Movement - immunology; Cytokines; Cytotoxicity; Development and progression; E-Selectin - metabolism; Health aspects; Humans; Hyperthermia, Induced; Intercellular Adhesion Molecule-1 - metabolism; Interleukin-6; Interleukin-6 - metabolism; Lymphocytes; Melanoma; Mice; Microvessels - immunology; Models, Immunological; Neoplasms - blood supply; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; P-Selectin - metabolism; Patients; Physiological aspects; Signal Transduction; T cells; T-Lymphocytes, Cytotoxic - immunology; Tumor Microenvironment - immunology; Tumorigenesis; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI44952

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.