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Updated: May 9, 2026

Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
07:44

Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports

Published on: November 28, 2019

An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy

Alicia S Chung1, Xiumin Wu, Guanglei Zhuang

  • 1Department of Research Drug Discovery, Genentech, Inc., South San Francisco, California, USA.

Nature Medicine
|August 6, 2013
PubMed

Insights

Interleukin-17 (IL-17) from T helper 17 (T(H)17) cells drives resistance to anti-angiogenic therapy by mobilizing immature myeloid cells. Blocking IL-17 or T(H)17 cells can restore sensitivity to VEGF inhibitors in resistant tumors.

Area of Science:

  • Immunology
  • Oncology
  • Molecular Biology

Background:

  • Angiogenesis inhibitors are vital cancer therapeutics but face limitations due to treatment resistance.
  • The tumor microenvironment significantly influences resistance, yet underlying mechanisms require further elucidation.

Purpose of the Study:

  • To investigate the paracrine signaling network between adaptive and innate immune systems contributing to resistance against anti-angiogenic therapy.
  • To identify specific immune cells and cytokines involved in mediating resistance to vascular endothelial growth factor (VEGF) inhibition.

Main Methods:

  • Utilized multiple tumor models (lymphoma, lung, colon) to study immune cell interactions and signaling pathways.
  • Investigated the role of T helper type 17 (T(H)17) cells and interleukin-17 (IL-17) in inducing granulocyte colony-stimulating factor (G-CSF) expression via NF-κB and ERK signaling.
  • Analyzed T(H)17 cells and Bv8-positive granulocytes in clinical tumor specimens.
  • Assessed tumor sensitivity to VEGF inhibitors in IL-17 receptor (IL-17R)-knockout hosts and following pharmacological blockade of T(H)17 cell function.

Main Results:

  • Uncovered a paracrine signaling network involving T(H)17 cells and IL-17 that promotes resistance to anti-angiogenic therapy.
  • IL-17 induced G-CSF expression through NF-κB and ERK signaling, leading to immature myeloid cell mobilization and recruitment into the tumor microenvironment.
  • T(H)17 cells and Bv8-positive granulocytes were present in clinical tumor samples.
  • IL-17R-knockout hosts and pharmacological inhibition of T(H)17 cells restored sensitivity to VEGF inhibitors in resistant tumors.

Conclusions:

  • Interleukin-17 (IL-17) plays a critical role in promoting tumor resistance to VEGF inhibition.
  • The identified IL-17-mediated signaling axis involving T(H)17 cells and myeloid cell recruitment represents a key mechanism of resistance.
  • Targeting IL-17 or T(H)17 cell function offers a potential immunomodulatory strategy to enhance the efficacy of anti-angiogenic therapies.

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