IL-6 trans-signaling promotes the expansion and anti-tumor activity of CAR T cells

Leukemia. 2021 May;35(5):1380-1391. doi: 10.1038/s41375-020-01085-1. Epub 2020 Nov 9.


Chimeric antigen receptor (CAR) T cell therapies lead to high clinical response rates in B cell malignancies, and are under investigation for treatment of solid tumors. While high systemic interleukin- (IL-) 6 levels are associated with clinical cytokine release syndrome (CRS), the role of IL-6 trans-signaling within CAR T-cells has not been reported. We generated CAR T cells that constitutively express hyper IL-6 (HIL-6), a designer cytokine that activates the trans-signaling pathway. HIL-6-expressing CAR T-cells exhibited enhanced proliferation and antitumor efficacy in vitro and in xenograft models. However, HIL-6 CAR T cells caused severe graft-versus-host disease (GVHD). Transcriptomic profiling revealed that HIL-6 stimulation of CAR T cells upregulated genes associated with T cell migration, early memory differentiation, and IL-6/GP130/STAT3 signaling. Since IL-6 trans-signaling acts via surface GP130, we generated CAR T cells expressing a constitutively-active form of GP130 and found these retained improved antitumor activity without signs of GVHD in preclinical models of B-cell leukemia and solid tumors. Taken together, these results show that IL-6 trans-signaling can enhance expansion and antitumor activity of CAR T cells via the GP130/STAT3 pathway, and suggest that expression of GP130 within CAR T cells could lead to improved antitumor efficacy without systemic IL-6 trans-signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Cell Proliferation / physiology
  • HEK293 Cells
  • Humans
  • Interleukin-6 / immunology*
  • Lymphocyte Activation / immunology
  • Mice
  • Receptors, Chimeric Antigen / immunology*
  • Signal Transduction / immunology*
  • T-Lymphocytes / immunology*
  • Xenograft Model Antitumor Assays / methods


  • Interleukin-6
  • Receptors, Chimeric Antigen