Harnessing NK Cells for Cancer Treatment

Abstract

In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. NK cells are innate lymphocytes with an array of functional competences, including anti-cancer, anti-viral, and anti-graft-vs.-host disease potential. The intriguing idea of harnessing such potent innate immune system effectors for cancer treatment led to the development of clinical trials based on the adoptive therapy of NK cells or on the use of monoclonal antibodies targeting the main NK cell immune checkpoints. Indeed, checkpoint immunotherapy that targets inhibitory receptors of T cells, reversing their functional blocking, marked a breakthrough in anticancer therapy, opening new approaches for cancer immunotherapy and resulted in extensive research on immune checkpoints. However, the clinical efficacy of T cell-based immunotherapy presents a series of limitations, including the inability of T cells to recognize and kill HLA-I^neg tumor cells. For these reasons, new strategies for cancer immunotherapy are now focusing on NK cells. Blockade with NK cell checkpoint inhibitors that reverse their functional block may overcome the limitations of T cell-based immunotherapy, mainly against HLA-I^neg tumor targets. Here, we discuss recent anti-tumor approaches based on mAb-mediated blocking of immune checkpoints (either restricted to NK cells or shared with T cells), used either as a single agent or in combination with other compounds, that have demonstrated promising clinical responses in both solid tumors and hematological malignancies.

Keywords: NK cell receptors; NK cells; adoptive NK cell therapy; hematological malignancies; immune checkpoint blockade; immunotherapy; solid tumors.

Figure 1

Mechanisms of NK cell-mediated killing. In physiological conditions, NK cell activity is tightly regulated by a complex interplay between inhibitory and activating receptors that prevents killing of normal autologous cells expressing an appropriate level of all self-HLA alleles and low/negative levels of ligands for non-HLA-specific activating receptors (aNKR) (A). Downregulation of HLA-I molecules on neoplastic or infected cells induces NK-mediated killing by a “missing-self” recognition mechanism. NK cell activating receptors are co-responsible in inducing NK cell triggering by interacting with ligands (aNKR-ligands) overexpressed or expressed de novo on tumor-transformed or virus-infected cells (B). Allogeneic (alloreactive) donor NK cells are able to kill neoplastic cells of the recipient expressing non-self allotypic determinants on HLA-I molecules (“KIR/KIR-ligand mismatch”) and to control infections with a limited risk of toxicity (e.g., GvHD and HvG) (C). The use of inhibitors of classical NK cell immune checkpoints (i.e., KIR and NKG2A) (D) or immune checkpoints shared with T cells (e.g., PD-1) (E) or, finally, a combination of these approaches represents new promising strategies in NK cell-based immunotherapy.