AUTHOR=Wang Yi , Jiang Hua , Luo Hong , Sun Yansha , Shi Bizhi , Sun Ruixin , Li Zonghai 

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

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.01691

DOI=10.3389/fimmu.2019.01691

ISSN=1664-3224

ABSTRACT=<p>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<sup>+</sup> 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 <italic>in vitro</italic>. Furthermore, 4/21 ICR-CAR T cells persisted and eradicated established IL-4<sup>+</sup> tumors <italic>in vivo</italic>. Thus, 4/21 ICR is a promising clinical CAR-T cell therapeutics for solid tumors rich in IL-4.</p>