Engineering advanced logic and distributed computing in human CAR immune cells

Nat Commun. 2021 Feb 4;12(1):792. doi: 10.1038/s41467-021-21078-7.

Abstract

The immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Communication / immunology
  • Cell Engineering / methods*
  • Cell Line, Tumor
  • Female
  • HEK293 Cells
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Mice
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Primary Cell Culture
  • Receptors, Chimeric Antigen / genetics*
  • Receptors, Chimeric Antigen / immunology
  • Receptors, Chimeric Antigen / metabolism
  • Recombinant Fusion Proteins / genetics*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Synthetic Biology / methods
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Receptors, Chimeric Antigen
  • Recombinant Fusion Proteins