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Engineering advanced logic and distributed computing in human CAR immune cells.

Nature communications (2021-02-06)
Jang Hwan Cho, Atsushi Okuma, Katri Sofjan, Seunghee Lee, James J Collins, Wilson W Wong
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Imidazole, for molecular biology, ≥99% (titration)
Sigma-Aldrich
Mitomycin C from Streptomyces caespitosus, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
N-Acetyl-L-cysteine, BioReagent, suitable for cell culture
USP
Zoledronic acid, United States Pharmacopeia (USP) Reference Standard