Engineering advanced logic and distributed computing in human CAR immune cells

• Published in: Nature communications 2021-02, Vol.12 (1), p.792-792, Article 792
• Main Authors: Cho, Jang Hwan, Okuma, Atsushi, Sofjan, Katri, Lee, Seunghee, Collins, James J., Wong, Wilson W.
• Format: Article
• Language: English
• Subjects: 13/106; 13/21; 13/31; 42/109; 42/35; 59/5; 631/250/251; 631/553/2691; 631/553/552; Adaptive systems; Animals; Antigens; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Communication - immunology; Cell Engineering - methods; Cell Line, Tumor; Cell signaling; Chimeric antigen receptors; Circuits; Computer networks; Consortia; Distributed processing; Engineering; Female; HEK293 Cells; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunotherapy, Adoptive - methods; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Lymphocytes; Lymphocytes T; Mice; multidisciplinary; Neoplasms - immunology; Neoplasms - pathology; Neoplasms - therapy; Phenotypes; 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; Science; Science (multidisciplinary); Synthetic Biology - methods; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21078-7

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. Most CAR designs lack control and computation features, limiting the sophistication of the engineered immune response. Here the authors leverage a split CAR design for engineering coordinated immune responses.