Current progress in NK cell biology and NK cell-based cancer immunotherapy

Abstract

A better understanding of the complex interactions between the immune system and tumour cells from different origins has opened the possibility to design novel procedures of antitumoral immunotherapy. One of these novel approaches is based on the use of autologous or allogeneic natural killer (NK) cells to treat cancer. In the last decade, different strategies to activate NK cells and their use in adoptive NK cell-based therapy have been established. Although NK cells are often considered as a uniform cell population, several phenotypic and functionally distinct NK cells subsets exist in healthy individuals, that are differentially affected by ageing or by apparently innocuous viruses such as cytomegalovirus (CMV). In addition, further alterations in the expression of activating and inhibitory receptors are found in NK cells from cancer patients, likely because of their interaction with tumour cells. Thus, NK cells represent a promising strategy for adoptive immunotherapy of cancer already tested in phase 1/2 clinical trials. However, the existence of NK cell subpopulations expressing different patterns of activating and inhibitory receptors and different functional capacities, that can be found to be altered not only in cancer patients but also in healthy individuals stratified by age or CMV infection, makes necessary a personalized definition of the procedures used in the selection, expansion, and activation of the relevant NK cell subsets to be successfully used in NK cell-based immunotherapy.

Keywords: Ageing; Cancer; Immunosenescence; NK cell-based immunotherapy; NK cells; PIVAC 19.

Fig. 1

Human NK cell subsets and receptors. a The expression of CD56 and CD16 defines 4 human NK cell subsets. b Human NK cells express a large panel of activating and inhibitory receptors. NK cell activation depends on the balance between inhibitory and activating receptors expressed on NK cell surface that interact with their ligands on tumour cells. The major inhibitory receptors recognize as ligands HLA class I molecules. Several non-HLA class I-specific inhibitory receptors are highly expressed on NK cells (e.g. TIGIT; TIM-3, LAG-3) and may represent checkpoints for NK cell activation. c A representative cytometry of peripheral blood NK cells in a healthy donor is shown

Fig. 2

Model of peripheral blood NK cell differentiation in healthy individuals and the effect of CMV. Altered expression of NK activating and inhibitory receptors and decreased NK cell cytotoxicity is often observed in cancer patients. Both ageing and cancer are associated with decreased cytotoxicity. Ageing is associated with decreased telomerase activity and telomere length in all NK cell subsets

Fig. 3

Enhancement of NK cell cytotoxic capacity for adoptive immunotherapy. Different strategies can be used to enhance the capacity of NK cells to kill tumour cells. Cytokines such as IL-2 and IL-15 are used to activate and expand NK cells in vitro and in vivo. The promotion of ADCC represent a valuable strategy by using mAb targeting tumour antigens (TAA) alone or in combination with low-dose IL-2 or using killer engagers that link CD16 on NK cells to tumour antigens (BiKE), that can also include IL-15 (TRiKE, TetraKE). Checkpoint blockade using mAb directed to HLA class I-specific inhibitory receptors (KIR and NKG2A) and non-HLA class I-specific inhibitory receptors (e.g. TIGIT, PVRIG, TIM-3, LAG-3) can be used to block inhibitory signals and activate NK cells. (PBMC: peripheral blood mononuclear cells, UCB: umbilical cord blood; BM; bone marrow; IPSs: induced pluripotent stem cells)