IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells
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
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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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 8

Antigen-restricted killing of tumor targets depends on CD8+ T cell trafficking across tumor vessels.

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Antigen-restricted killing of tumor targets depends on CD8+ T cell traff...
(A) Growth curves of B16-OVA tumors in mice treated with STT and adoptive cell transfer (ACT) of OT-I effector cells. Treatment times are denoted by arrows; numbers above arrows indicate tumor volume at the time of treatment. n = 5 mice per condition. *P < 0.04 versus NT plus ACT. (B) Representative photomicrographs of B16-OVA tumors 12 hours after adoptive transfer of TRITC-labeled OT-I cells (red). Apoptotic cells were detected by TUNEL assay (green), and nucleated cells were stained with DAPI (blue). Scale bar: 100 μm. Quantification of intratumoral TRITC+ OT-I cells and TUNEL+ apoptotic cells at 1 or 12 hours after adoptive transfer is also shown. (C) Neutralizing antibody specific for IL-6 or E/P-selectin was administered intravenously 30 minutes before STT treatment in B16-OVA tumor–bearing WT mice. Tumors were also implanted in Icam1–/– mice. (B and C) Data are from individual mice and are representative of at least 3 independent experiments. *P < 0.002 versus NT.