An IL-4/21 Inverted Cytokine Receptor Improving CAR-T Cell Potency in Immunosuppressive Solid-Tumor Microenvironment

Front Immunol. 2019 Jul 19:10:1691. doi: 10.3389/fimmu.2019.01691. eCollection 2019.

Abstract

Incorporation of inverted cytokine receptor (ICR) such as interleukin (IL)-4 vs. IL-7 (4/7) ICR is one strategy to improve the antitumor activities of chimeric antigen receptor (CAR) modified T (CAR-T) cells facing immunosuppressive cytokines. Here we report a novel interleukin (IL)-4 vs. IL-21 ICR (4/21 ICR) that enhanced CAR-T cell potency in IL-4+ tumor milieu via a different working-mechanism from 4/7 ICR. Upon IL-4 stimulation, 4/21 ICR activated the STAT3 pathway and promoted Th17-like polarization and tumor-targeted cytotoxicity in CAR-T cells in vitro. Furthermore, 4/21 ICR-CAR T cells persisted and eradicated established IL-4+ tumors in vivo. Thus, 4/21 ICR is a promising clinical CAR-T cell therapeutics for solid tumors rich in IL-4.

Keywords: CAR-T cells; immunosuppressive tumor microenvironment; interleukin-21; interleukin-4; inverted cytokine receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Female
  • Humans
  • Immune Tolerance
  • Immunotherapy, Adoptive*
  • Interleukin-4 / immunology*
  • Mice
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, Chimeric Antigen / immunology*
  • Receptors, Interleukin-21 / immunology*
  • Receptors, Interleukin-4 / immunology*
  • T-Lymphocytes / immunology
  • Tumor Microenvironment / immunology

Substances

  • Receptors, Chimeric Antigen
  • Receptors, Interleukin-21
  • Receptors, Interleukin-4
  • Interleukin-4