Tumor immunotherapy: New aspects of natural killer cells

Abstract

A group of impressive immunotherapies for cancer treatment, including immune checkpoint-blocking antibodies, gene therapy and immune cell adoptive cellular immunotherapy, have been established, providing new weapons to fight cancer. Natural killer (NK) cells are a component of the first line of defense against tumors and virus infections. Studies have shown dysfunctional NK cells in patients with cancer. Thus, restoring NK cell antitumor functionality could be a promising therapeutic strategy. NK cells that are activated and expanded ex vivo can supplement malfunctional NK cells in tumor patients. Therapeutic antibodies, chimeric antigen receptor (CAR), or bispecific proteins can all retarget NK cells precisely to tumor cells. Therapeutic antibody blockade of the immune checkpoints of NK cells has been suggested to overcome the immunosuppressive signals delivered to NK cells. Oncolytic virotherapy provokes antitumor activity of NK cells by triggering antiviral immune responses. Herein, we review the current immunotherapeutic approaches employed to restore NK cell antitumor functionality for the treatment of cancer.

Keywords: Natural killer cells; immunotherapy; neoplasms.

1

Immune surveillance of cancer by natural killer (NK) cells. (A) NK cells are activated via the engagement of activating receptors with induced ligands expressed on cancer cells; (B) Loss of the expression of human leukocyte antigens (HLAs) on cancer cells releases NK cell cytotoxicity due to a lack of inhibitory signals; (C) NK cells process antibody-dependent cell-mediated cytotoxicity (ADCC) effects to kill tumor cells with tumor-associated antigen (TAA)-specific antibodies; (D) Activated NK cells kill cancer cells via multiple approaches.

2

Mechanism of tumor immune escape from NK cells. (A) Cancer cells escape NK cell surveillance by decreasing the expression of activating receptor ligands or generating soluble activating receptor ligands to block recognition; (B) Preserving the expression of HLAs on cancer cells inhibits NK cell activation; (C) Suppressive immune cells and molecules inhibit NK cell activation; (D) Cancer cell evasion occurs when NK cells are compromised.

3

Immunotherapeutic strategies for restoring NK cell antitumor responsiveness. (A) Blocking soluble activating receptor ligands and inducing cancer cells to express membrane-bound ligands [with an oncolytic virus (O.V.)] facilitate NK cell activation; (B) Blockade of inhibitory NK cell receptors with therapeutic antibodies or haploidentical transplantation reduces inhibitory signaling to NK cells; (C) Retargeting strategies involving therapeutic antibodies, bispecific engagement or chimeric antigen receptors (CARs) enhance NK cell-mediated antitumor activation; (D) Restoration of NK cells via immunotherapy eliminates cancer cells again.