Synthetic cytokine circuits that drive T cells into immune-excluded tumors

Science. 2022 Dec 16;378(6625):eaba1624. doi: 10.1126/science.aba1624. Epub 2022 Dec 16.


Chimeric antigen receptor (CAR) T cells are ineffective against solid tumors with immunosuppressive microenvironments. To overcome suppression, we engineered circuits in which tumor-specific synNotch receptors locally induce production of the cytokine IL-2. These circuits potently enhance CAR T cell infiltration and clearance of immune-excluded tumors, without systemic toxicity. The most effective IL-2 induction circuit acts in an autocrine and T cell receptor (TCR)- or CAR-independent manner, bypassing suppression mechanisms including consumption of IL-2 or inhibition of TCR signaling. These engineered cells establish a foothold in the target tumors, with synthetic Notch-induced IL-2 production enabling initiation of CAR-mediated T cell expansion and cell killing. Thus, it is possible to reconstitute synthetic T cell circuits that activate the outputs ultimately required for an antitumor response, but in a manner that evades key points of tumor suppression.

MeSH terms

  • Animals
  • Cell Engineering
  • Humans
  • Immunosuppression Therapy* / methods
  • Immunotherapy, Adoptive* / methods
  • Interleukin-2* / genetics
  • Interleukin-2* / metabolism
  • Mice
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / metabolism
  • Receptors, Notch / metabolism
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / transplantation
  • Tumor Microenvironment


  • Interleukin-2
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Receptors, Notch