Chimeric antigen receptor- and natural killer cell receptor-engineered innate killer cells in cancer immunotherapy

Abstract

Chimeric antigen receptor (CAR)-engineered T-cell (CAR-T) therapy has demonstrated impressive therapeutic efficacy against hematological malignancies, but multiple challenges have hindered its application, particularly for the eradication of solid tumors. Innate killer cells (IKCs), particularly NK cells, NKT cells, and γδ T cells, employ specific antigen-independent innate tumor recognition and cytotoxic mechanisms that simultaneously display high antitumor efficacy and prevent tumor escape caused by antigen loss or modulation. IKCs are associated with a low risk of developing GVHD, thus offering new opportunities for allogeneic "off-the-shelf" cellular therapeutic products. The unique innate features, wide tumor recognition range, and potent antitumor functions of IKCs make them potentially excellent candidates for cancer immunotherapy, particularly serving as platforms for CAR development. In this review, we first provide a brief summary of the challenges hampering CAR-T-cell therapy applications and then discuss the latest CAR-NK-cell research, covering the advantages, applications, and clinical translation of CAR- and NK-cell receptor (NKR)-engineered IKCs. Advances in synthetic biology and the development of novel genetic engineering techniques, such as gene-editing and cellular reprogramming, will enable the further optimization of IKC-based anticancer therapies.

Keywords: Adoptive cell therapy; Chimeric antigen receptor; Genetic engineering; Innate killer cells; Natural killer cell receptor; Tumor microenvironment.

Fig. 1

Through their extracellular scFv domain, CAR- and NKR-engineered NK cells. CAR-engineered NK cells specifically target TAAs expressed on tumor cells. They exert cytolytic activity against tumor cells in both a CAR-dependent and CAR-independent (through NKR recognition of NKR ligands and through CD16-mediated ADCC effect) manner. NKR-engineered NK cells can target a wide spectrum of tumor types with high expression of NKR ligands through NKRs. Activated receptor-modified NKR-NK cells (such as NKG2D-, NKp30- or DNAM-1-engineered NK cells) exhibit direct cytotoxicity against tumors with high expression of NKR ligands. Inhibitory NKR-modified NK cells can target tumors that express high levels of corresponding inhibitory ligands such as PD-L1. Modification with a truncated DN inhibitory receptor (e.g., DN PD-1), lacking its intracellular signaling domains, can resist checkpoint receptor-induced cell exhaustion. Inhibitory switch receptors containing an extracellular domain of inhibitory receptors (e.g., PD-1) and intracellular activating costimulatory domains (e.g., CD28) in engineered NK cells enable checkpoint receptor-mediated inhibitory signals to be switched to activating signals, thus reversing TME-mediated immunosuppression. The potential of inhibitory switch receptors, including PD-1, TIGIT, and NKG2A, used alone or in combination with other strategies for the treatment of solid tumors is under investigation

Fig. 2

CAR- and NKR-engineered innate killer cells. IKCs can be engineered to express CAR and NKR, giving rise to CAR- or NKR-engineered IKCs with more powerful tumor targeting and efficient cytolytic capacity to kill tumor cells. CAR- or NKR-engineered NK cells exert direct cytolysis against tumor cells in both a CAR- and NKR-dependent manner and through antibody-dependent cellular cytotoxicity (ADCC). NKT cell activation depends on the recognition of glycosphingolipids, glycolipids, or lipid antigens (e.g., α-GalCer). CAR-engineered NKT cells exhibit a more effective antitumor immune response and are able to eradicate tumor cells in both a CAR- and CD1d-dependent manner. γδ T cells recognize phosphoantigens (pAgs). They can be engineered to include a CAR or NKR, thus driving direct antitumor responses through CAR or NKR recognition and by ADCC