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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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 1

Homeostatic and thermally inducible trafficking of CD8+ T cells at organ sites in NT control and STT-treated mice.

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Homeostatic and thermally inducible trafficking of CD8+ T cells at organ...
(A) Photomicrographs of immunostained endogenous CD8+ T cells (arrowheads denote CD8+ T cells in melanin+ B16 tumors), and quantification of CD8+ T cell infiltration. (B) Infiltration of leukocyte subsets in B16-OVA tumors; CD8+ T cells (CD8+CD3+), CD4+ T cells (CD4+CD3+), Tregs (CD4+CD25+FoxP3+), granulocytic MDSCs (CD11b+Ly6G+Ly6Clo), monocytic MDSCs (CD11b+Ly6ChiLy6G–); polymorphonuclear cells (PMNs; CD11b+ Ly6G+ Ly6C–), and macrophages (MΦ, CD11b+Ly6C–Ly6G–). Data are pooled tumors (3 per group) from 5 independent experiments. (C and D) Short-term (1 hour) homing of TK1 cells (C) or activated OT-I T cells (D) to mesenteric LNs (MLNs), Peyer patches (PP), tumor, pancreas (Panc), and kidney. (C) Representative photomicrographs and quantification of TRITC-labeled TK1 CD8+ T cells (red) in tissues counterstained for CD31+ vessels (green). (D) Quantification of TRITC-labeled OT-I T cells in B16-OVA tumor–bearing mice by microscopy. Representative dot plots show the phenotype of TRITC-labeled OT-I T cells that trafficked into LNs and tumors. CD62L is L-selectin. Data are based on analysis of equivalent numbers of transferred CD8+ T cells in pooled samples (n = 3 mice); numbers denote percent positive cells. (A, C, and D) Data are representative of at least 3 independent experiments. *P < 0.01, #P < 0.05, NT versus STT. Scale bars: 100 μm.