TCR-NK Cells: A Novel Source for Adoptive Immunotherapy of Cancer.

Abstract

Antigen-specific retargeting of cytotoxic lymphocytes against tumor-associated antigens has so far remained largely dependent on chimeric antigen receptors (CARs) that can be constructed by the fusion of an extracellular targeting domain (classically an scFv fragment from an antibody) fused with intracellular signaling domains to trigger activation of T or NK cells. A major limitation of CAR-based therapies is that this technology allows only for targeting antigens that would be located on the surface of a target cell while non-surface antigens that constitute about ¾ of all human genes stay out-of-reach. The targeting of non-surface antigens is only possible by using the inherent mechanisms of the T cell receptor (TCR). However, introducing a second TCR into T cells via genetic modification has been problematic due to the heterodimeric nature of the TCR ligand-binding domain that is composed of TCR α and β chains. It has been observed that the delivery of a second TCR α/β pair to may lead to mispairing of new TCR chains with the endogenously expressed ones and create mixed TCR dimers which has negatively affected the advancement of TCR-based T cell therapies. Recently, Natural Killer (NK) cells have been put forward as effectors for TCR gene therapy. Since NK cells do not endogenously express TCR chains, this seems to be an infallible method in circumventing the mispairing problem. Moreover, the similarity of intracellular signaling pathways and mechanisms of cytotoxicity between NK and T cells makes sure that the triggering of antigen-specific responses by the TCR/CD3 complex can be used to induce antigen-specific cytotoxicity by TCR-modified NK cells (TCR-NK). This review aims to overview the initial studies on TCR-NK cells, identify open questions in the field and define its place within the spectrum of adoptive immunotherapy approaches that rely on cytotoxic lymphocytes.