Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy

Abstract

The incidence of some types of tumours has increased progressively in recent years and is expected to continue growing in the coming years due in part to the aging of the population. The design of new therapies based on natural killer (NK) cells opens new possibilities especially for the treatment of elderly patients who are particularly susceptible to the toxicity of conventional chemotherapy treatments. In recent years, the potential use of NK cells in cancer immunotherapy has been of great interest thanks to advances in the study of NK cell biology. The identification of key points (checkpoints) in the activation of NK cells that can be regulated by monoclonal antibodies has allowed the design of new therapeutic strategies based on NK cells. However, there are still limitations for its use and the first clinical trials blocking KIR inhibitory receptors have shown little efficacy by inhibiting the maturation of NK cells. Blockade of other inhibitory receptors such as TIGIT, TIM3, LAG3 and PD1 may represent novel strategies to increase NK function in cancer patients. Altogether, the identification of NK cell and tumour cell markers of resistance or susceptibility to the action of NK cells will contribute to identifying those patients that will most likely benefit from NK cell-based immunotherapy.

Keywords: Checkpoint blockade; Immunotherapy; NK cells; PIVAC 17; miRNA.

Fig. 1

Activating and inhibitory signals control NK cell effector functions. NK cell recognition of tumour cells depends on the balance between different receptors expressed on NK cells that interact with their ligands on tumour cells (a). Inhibitory signals are mediated by MHC class I-specific receptors (KIR and NKG2A) and other receptors TIM3 (ligand Ceacam-1), LAG3 (ligand LSECtin), TIGIT (ligands CD112 and CD155), TACTILE (ligand CD155), recognizing ligands other than MHC class I molecules. The major activating receptors include DNAM-1 (ligands CD112 and CD155), NCRs NK30 (ligand B7H6), NKp46 and NKp44 and NKG2D (ligands ULBPs and MICA/B) whose ligands are frequently overexpressed on virus infected and tumour cells. Checkpoint blockade by mAb and immunomodulation of NK cell activation and function represent strategies for immunotherapy based on NK cells. Clinical trials using mAb against KIR, NKG2A, TIM-3, LAG-3 and TIGIT are undergoing (b). Blocking of inhibitory signals can enhance NK cell activation leading to tumour cell destruction mediated by granzymes and perforin release into immunological synapse