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- Title
IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells.
- Authors
Fisher, Daniel T.; Qing Chen; Skitzki, Joseph J.; Muhitch, Jason B.; Lei Zhou; Appenheimer, Michelle M.; Vardam, Trupti D.; Weis, Emily L.; Passanese, Jessica; Wan-Chao Wang; Gollnick, Sandra O.; Dewhirst, Mark W.; Rose-John, Stefan; Repasky, Elizabeth A.; Baumann, Heinz; Evans, Sharon S.; Chen, Qing; Zhou, Lei; Wang, Wan-Chao
- 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.
- Subjects
CYTOKINES; IMMUNOTHERAPY; T cells; PROTEINS; TUMORS; TUMOR treatment; ANIMAL experimentation; ANTIGENS; APOPTOSIS; BIOLOGICAL models; BLOOD vessels; CELL lines; CELL physiology; CELL motility; CELLULAR signal transduction; COMPARATIVE studies; INTERLEUKINS; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; THERMOTHERAPY; EVALUATION research
- Publication
Journal of Clinical Investigation, 2011, Vol 121, Issue 10, p3846
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI44952