Immunological and Translational Aspects of NK Cell-Based Antitumor Immunotherapies

Abstract

Natural killer (NK) cells play a pivotal role in the first line of defense against cancer. NK cells that are deficient in CD3 and a clonal T cell receptor (TCR) can be subdivided into two major subtypes, CD56^dimCD16⁺ cytotoxic and CD56^brightCD16^- immunoregulatory NK cells. Cytotoxic NK cells not only directly kill tumor cells without previous stimulation by cytotoxic effector molecules, such as perforin and granzymes or via death receptor interactions, but also act as regulatory cells for the immune system by secreting cytokines and chemokines. The aim of this review is to highlight therapeutic strategies utilizing autologous and allogenic NK cells, combinations of NK cells with monoclonal antibodies to induce antibody-dependent cellular cytotoxicity, or immune checkpoint inhibitors. Additionally, we discuss the use of chimeric antigen receptor-engineered NK cells in cancer immunotherapy.

Keywords: antibody-dependent cellular cytotoxicity; checkpoint inhibitors; chimeric antigen receptor; immunotherapy; monoclonal antibody; natural killer cell.

Figure 1

NK cells-based immunotherapeutic concepts. (A) NK cell stimulation approach. Antibody-mediated blockade of the inhibitory receptors expressed on the cell membrane of NK cells as well as stimulation of the activating receptors results in an increased cytolytic activity of NK cells. (B) Antibody-dependent cellular cytotoxicity (ADCC) therapies. Binding of the FcγR to the Fc fragment of the antibody (left) results in the activation of NK cells and induces the release of effector molecules such as perforin and granzyme. Application of bispecific antibodies (right) directed against CD16 (on NK cells) and tumor antigens facilitate conjugate formation of NK cells with tumor cells. (C) Chimeric antigen receptor (CAR)-engineered NK cells. CAR consists of an external recognition domain [i.e., small chain variable fragment (scFv)] that recognizes the tumor-specific antigen, a transmembrane domain, and an intracellular signaling domain (CD3-ζ chain) that induces NK cell activation.