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

J Clin Invest. 2011 Oct;121(10):3846-59. doi: 10.1172/JCI44952. Epub 2011 Sep 19.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Cell Line, Tumor
  • Cell Movement / immunology
  • E-Selectin / metabolism
  • Humans
  • Hyperthermia, Induced
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-6 / metabolism*
  • Mice
  • Microvessels / immunology
  • Models, Immunological
  • Neoplasms / blood supply*
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neoplasms / therapy
  • P-Selectin / metabolism
  • Signal Transduction
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Microenvironment / immunology

Substances

  • E-Selectin
  • IL6 protein, human
  • Interleukin-6
  • P-Selectin
  • Intercellular Adhesion Molecule-1