title: 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.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Fisher
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Skitzki
authors.forename: Jason B
authors.initials: JB
authors.lastname: Muhitch
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Appenheimer
authors.forename: Trupti D
authors.initials: TD
authors.lastname: Vardam
authors.forename: Emily L
authors.initials: EL
authors.lastname: Weis
authors.forename: Jessica
authors.initials: J
authors.lastname: Passanese
authors.forename: Wan-Chao
authors.initials: WC
authors.lastname: Wang
authors.forename: Sandra O
authors.initials: SO
authors.lastname: Gollnick
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Repasky
authors.forename: Heinz
authors.initials: H
authors.lastname: Baumann
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Evans
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D019040:E-Selectin / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D055806:Microvessels / Q000276:immunology; D018448:Models, Immunological; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D019007:P-Selectin / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D019040:E-Selectin; C508600:IL6 protein, human; D015850:Interleukin-6; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1