Enhancing CAR T-Cell Function with Domains of Innate Immunity Sensors

Abstract

The innate immune system plays an important role in protecting the organism via recognizing the danger signals and pathogens through pattern recognition receptors. By sensing the danger signal and conveying the signaling towards the elimination of the threat, several families of these receptors, expressed on different myeloid and innate lymphoid cells, serve as the first defense line in the innate immunity. Toll-like receptors, C-type lectin receptors, and many other receptors therefore illustrate the importance of the protective role of the immune system. This was additionally confirmed by CAR T-cell-based cancer immunotherapy, where the patient's own immune system is being used for successful tumor elimination. CAR T-cells have proven themselves to be a potent therapeutic option, yet in some cases their efficiency could be enhanced. Innate immune sensors that include strong activation and signaling domains, for instance, part of the Toll-like receptors, MyD88 (Myeloid Differentiation Primary Response gene), NKG2D (Natural killer group 2-member D), and many other domains, could be used as a CAR building module to increase the functionality and potency of the CAR T-cells.

Keywords: CAR T-cell; Toll-like receptor domains; cancer immunotherapy; innate immune system.

Figure 1

Schematic representation of CAR constructs with innate immunity signaling domains. (a) CAR incorporating the TLR2 domain alongside CD28 and CD3ζ (zeta) domains for activation and co-stimulation. (b) Membrane-bound D569-TLR4 coexpressed with a CAR containing 4-1BB and CD3ζ signaling domains. (c) TRIF NTD-TIR fused with a CAR containing 4-1BB and CD3ζ signaling domains. (d) Coexpression of MyD88 with a CAR containing 4-1BB and CD3ζ domains. (e) Constitutive and inducible CAR design incorporating MyD88, CD40, and CD3ζ signaling domains.

Figure 2

Schematic representation of NKG2D-targeting CAR constructs. (a) CAR construct incorporating only the extracellular recognition domains of NKG2D, enabling target-specific antigen recognition. (b) CAR construct incorporating the full-length NKG2D receptor, which facilitates both antigen recognition and endogenous downstream signaling through NKG2D-associated pathways.