IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells
Daniel T. Fisher, … , Heinz Baumann, Sharon S. Evans
Daniel T. Fisher, … , Heinz Baumann, Sharon S. Evans
Published September 19, 2011
Citation Information: J Clin Invest. 2011;121(10):3846-3859. https://doi.org/10.1172/JCI44952.
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Research Article Immunology

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

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Figure 6

Vascular response to H-IL-6 in murine and patient tumors.

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Vascular response to H-IL-6 in murine and patient tumors. (A) Immunofluo...
(A) Immunofluorescence staining of pSTAT3 (red) in CD31+ (green) B16-OVA tumor vessels 15 minutes after intravenous administration of H-IL-6 fusion protein. Nuclei were stained with DAPI (blue). Microscopic quantification of pSTAT3 staining in CD31+ ECs is also shown; data are representative of 3 independent experiments. Scale bar: 50 μm. *P < 0.001 versus control. (B) OT-I interactions with B16-OVA tumor vessels 6 hours after H-IL-6 treatment; data are from 3 independent experiments. Intravascular staining of ICAM-1 (red) on CD31+ (green) B16-OVA tumor vessels 6 hours after H-IL-6 treatment is also shown. Scale bar: 100 μm. *P < 0.001, #P < 0.03 versus control. (C) Representative photomicrographs of immunofluorescence staining of ICAM-1 on CD31+ vessels in tumor explants of patient 1 (P1) after treatment with H-IL-6 for 6 hours. ICAM-1 and CD31 expression in 3 patient tumor explants is shown by histograms representing quantitative image analysis of the immunofluorescence intensity of adhesion molecules in CD31+ vessels. Numbers in photomicrographs and histograms are MFI. IL-6 concentration in patient tumor explants is also shown. Scale bar: 100 μm.