NK Cell-Based Immunotherapy in Colorectal Cancer

Abstract

Human Natural Killer (NK) cells are all round players in immunity thanks to their powerful and immediate response against transformed cells and the ability to modulate the subsequent adaptive immune response. The potential of immunotherapies based on NK cell involvement has been initially revealed in the hematological setting but has inspired the design of different immune tools to also be applied against solid tumors, including colorectal cancer (CRC). Indeed, despite cancer prevention screening plans, surgery, and chemotherapy strategies, CRC is one of the most widespread cancers and with the highest mortality rate. Therefore, further efficient and complementary immune-based therapies are in urgent need. In this review, we gathered the most recent advances in NK cell-based immunotherapies aimed at fighting CRC, in particular, the use of monoclonal antibodies targeting tumor-associated antigens (TAAs), immune checkpoint blockade, and adoptive NK cell therapy, including NK cells modified with chimeric antigen receptor (CAR-NK).

Keywords: CAR-NK cells; CRC; NK cells; bispecific antibodies; immune checkpoints; immunotherapies; monoclonal antibodies; trispecific engagers.

Figure 1

Main inhibitory (A) and activating (B) NK-cell surface receptors and their cognate ligands on target cells.

Figure 2

Strategies to enhance anti-tumor NK cell function against Colorectal Cancer (CRC). (a) ADCC triggering strategies via anti-TAA mAbs, BiKe, or NKCEs; (b) IC blockade via anti-NKG2A and anti-PD-1 mAbs; (c) Cytokine activation of NK cells by IL-2, IL-15/IL-12/IL-18 combination, or N-803; (d) CAR-modified NK cells targeting several TAAs (CEA, MUC-1, EpCAM, HER-2, and NKG2D ligands MICA/B and ULBPs).