Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV

Abstract

Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells contribute to the body's immune defenses. Current chimeric antigen receptor (CAR)-modified T cell immunotherapy shows strong promise for treating various cancers and infectious diseases. Although CAR-modified NK cell immunotherapy is rapidly gaining attention, its clinical applications are mainly focused on preclinical investigations using the NK92 cell line. Despite recent advances in CAR-modified T cell immunotherapy, cost and severe toxicity have hindered its widespread use. To alleviate these disadvantages of CAR-modified T cell immunotherapy, additional cytotoxic cell-mediated immunotherapies are urgently needed. The unique biology of NK cells allows them to serve as a safe, effective, alternative immunotherapeutic strategy to CAR-modified T cells in the clinic. While the fundamental mechanisms underlying the cytotoxicity and side effects of CAR-modified T and NK cell immunotherapies remain poorly understood, the formation of the immunological synapse (IS) between CAR-modified T or NK cells and their susceptible target cells is known to be essential. The role of the IS in CAR T and NK cell immunotherapies will allow scientists to harness the power of CAR-modified T and NK cells to treat cancer and infectious diseases. In this review, we highlight the potential applications of CAR-modified NK cells to treat cancer and human immunodeficiency virus (HIV), and discuss the challenges and possible future directions of CAR-modified NK cell immunotherapy, as well as the importance of understanding the molecular mechanisms of CAR-modified T cell- or NK cell-mediated cytotoxicity and side effects, with a focus on the CAR-modified NK cell IS.

Keywords: HIV; cancer; chimeric antigen receptor; immunological synapse; immunotherapy; natural killer cell.

Figure 1

The CAR-modified NK cell IS. (A) One CAR-modified NK92 cell (blue) interacts with a tumor cell (yellow) through an IS. (B) Two CAR-modified NK92 cells (blue) interact with a tumor cell (yellow) through two different ISs. These are two representative scanning electron micrographs using two different colors

Figure 2

CAR-modified NK cell ISs on a glass-supported, planar lipid bilayer. (A) Schematic depiction of a TIRF setup in which a lipid bilayer contains a fluorescence dye-labeled tumor antigen (green). TIRF (B), brightfield (C), and merge (D) images of CAR-modified NK cell IS formation on a glass-supported, planar lipid bilayer carrying an Alexa488-labled human CD19 protein (green). The three CAR-modified NK cells that contacted the lipid bilayer, as determined by the central accumulation of tumor antigen under TIRF microscopy, are numbered. Representative TIRF (E) and merge (F) images of CAR-modified NK cells are shown. Four individual CAR-modified NK cells, fixed at 30 min after addition to the bilayer carrying CD19-Alexa Fluor 488, are numbered. The images are representative of at least 100 cells from three independent experiments