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Chimeric Antigen Receptor-Engineered Natural Killer and Natural Killer T Cells for Cancer Immunotherapy


Chimeric Antigen Receptor-Engineered Natural Killer and Natural Killer T Cells for Cancer Immunotherapy

Dominique Bollino et al. Transl Res.


Natural killer (NK) cells of the innate immune system and natural killer T (NKT) cells, which have roles in both the innate and adaptive responses, are unique lymphocyte subsets that have similarities in their functions and phenotypes. Both cell types can rapidly respond to the presence of tumor cells and participate in immune surveillance and antitumor immune responses. This has incited interest in the development of novel cancer therapeutics based on NK and NKT cell manipulation. Chimeric antigen receptors (CARs), generated through the fusion of an antigen-binding region of a monoclonal antibody or other ligand to intracellular signaling domains, can enhance lymphocyte targeting and activation toward diverse malignancies. Most of the CAR studies have focused on their expression in T cells; however, the functional heterogeneity of CAR T cells limits their therapeutic potential and is associated with toxicity. CAR-modified NK and NKT cells are becoming more prevalent because they provide a method to direct these cells more specifically to target cancer cells, with less risk of adverse effects. This review will outline current NK and NKT cell CAR constructs and how they compare to conventional CAR T cells, and discuss future modifications that can be explored to advance adoptive cell transfer of NK and NKT cells.

Conflict of interest statement

Conflict of Interest and Financial Disclosure Statement: The authors declare that they have no competing interests.


Figure 1
Figure 1
Enhancement of NK-cell antitumor activity by the expression of chimeric antigen receptors. The natural cytotoxicity of natural killer (NK) cells is regulated by signals from stimulatory and inhibitory receptors. Under normal conditions, signaling from inhibitory receptors for MHC-I overpower stimulation through activation receptors. When cells lack or downregulate MHC-1 expression, activation receptors signal NK cytoxicity. Activation against self can occur when the target cell is stressed and upregulates ligands for activation receptors, thereby overcoming MHC class I inhibitory signaling. The expression of a chimeric antigen receptor (CAR) specific for tumor-associated cell surface antigens efficiently redirects NK cells to malignant cells, and facilitates their cytolytic activity independently from the activation of endogenous stimulatory receptors.
Figure 2
Figure 2
Activated NKT cells can mount both direct and indirect anti-tumor responses. Following activation, NKT cells rapidly secrete cytokines, such as IFN-γ, which can promote the activation of NK cells and CD8+ T cells, and in combination with CD40/CD40L interactions can also lead to the maturation of dendritic cells which can secrete IL-12 and further enhance NK and CD8+ T cell activation. NKT cells can also directly mediate cytotoxicity through FAS/FASL, perforin, and granzyme. NKT cells may be directed towards tumor cells expressing specific antigen through the transduction and expression of chimeric antigen receptors (CAR). CARs have an extracellular antigen-targeting domain capable of binding their target antigen in an MHC-independent manner. Current research efforts are focused on harnessing the adaptability of CARs to enhance NKT cell targeting of tumors.

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