Thymic NK-Cells and Their Potential in Cancer Immunotherapy

Abstract

Natural killer (NK)-cells are innate immune cells with potent anti-tumor capacity, capable of recognizing target cells without prior exposure. For this reason, NK-cells are recognized as a useful source of cell therapy. Although most NK-cells are derived from the bone marrow (BM), a separate developmental pathway in the thymus also exists, producing so-called thymic NK-cells. Unlike conventional NK-cells, thymic NK (tNK)-cells have a combined capacity for cytokine production and a natural ability to kill tumor cells in the presence of NK-cell receptor stimulatory ligands. Furthermore, tNK-cells are reported to express CD3 subunits intracellularly, without the presence of a rearranged T-cell receptor (TCR). This unique feature may enable harnessing of these cells with a TCR to combine NK- and T-cell effector properties in one cell type. The development, phenotype, and function of tNK-cells, and potential as a cell therapy is, however, poorly explored. In this review, we provide an overview of current literature on both murine and human tNK-cells in comparison to conventional BM-derived NK-cells, and discuss the potential applications of this cellular subset in the context of cancer immunotherapy.

Keywords: T-cell receptor; cancer immunotherapy; gene engineering; tumor immunogenicity.

Figure 1

Proposed Model of tNK-cell Development. This model proposes the process of human tNK-cell development, based on existing murine and human research. Common lymphoid progenitors (CLP) seed the thymus in the form of NKPs or ETPs, the latter of which will form DN thymocytes. DN thymocytes will progress through typical stages of T-cell development, forming DN1 and DN2 thymocytes. These cells act as TNKP, thus can follow a pathway of NK or T-cell lineage commitment. NKP are also speculated to migrate from the BM (red arrow) and immediately follow the (thymic) NK-cell fate. The steps in tNK-cell development are unique to that seen in the BM, also involving different cytokines and resulting in the upregulation of different markers. Figure created with BioRender.com.

Figure 2

The Potential of tNK-cells in Anti-Cancer Immunotherapy. (A) tNK-cells combine the cytokine-releasing potential of immature, CD56^brightCD16⁻ conventional NK-cells with the cytotoxic potential of mature, CD56^dimCD16⁺ conventional NK-cells, making them a unique cell source for NK-cell based therapies. (B) Evasion of MHC-I plasticity-mediated immune escape via TCR introduction in tNK-cells. T-cell cytotoxicity is evaded by low MHC-I expression, while tumor cells are subject to missing-self recognition by tNK-cells. Missing-self recognition results in IFN-γ secretion by NK-cells, triggering MHC-I expression on tumor cells, thereby evading missing-self mediated cytotoxicity by NK-cells. iCD3 expression in the tNK-cells provides a unique window to combine missing-self- and antigen-dependent cytotoxicity, thereby circumventing MHC-I plasticity-mediated immune escape. Figure created with BioRender.com.