An inverted cytokine receptor (ICR) comprised of the ecto-domain of IL-4 and the endo-domain of IL-21 (4/21 ICR) was used to modify hepatoma-targeting CAR T cells. IL-4-stimulated 4/21 ICR CAR T cells activated STAT3 and upregulated expression of IL-21 target genes RORγt and CD26, consistent with a Th17 phenotype. In vitro, 4/21 ICR CAR T cells efficiently lysed IL-4-producing tumor lines with minimal expression of exhaustion markers. In NOD mice, IL-4-expressing solid tumors were more efficiently eliminated by 4/21 CAR T cells than by control CAR T cells, suggesting enhanced potency in immunosuppressive IL-4 TME.
Contributed by Samuel Goldman
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.
Author Info: (1) State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Renji Hosptial, Shanghai Jiao Tong University, Shanghai, China. (2) State Key Laboratory
Author Info: (1) State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Renji Hosptial, Shanghai Jiao Tong University, Shanghai, China. (2) State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (3) State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Renji Hosptial, Shanghai Jiao Tong University, Shanghai, China. (4) State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (5) State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (6) State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. (7) State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Renji Hosptial, Shanghai Jiao Tong University, Shanghai, China. State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
