Human NK cells: from surface receptors to the therapy of leukemias and solid tumors

Abstract

Natural Killer (NK) cells are major effector cells of the innate immunity. The discovery, over two decades ago, of major histocompatibility complex-class I-specific inhibitory NK receptors and subsequently of activating receptors, recognizing ligands expressed by tumor or virus-infected cells, paved the way to our understanding of the mechanisms of selective recognition and killing of tumor cells. Although NK cells can efficiently kill tumor cells of different histotypes in vitro, their activity may be limited in vivo by their inefficient trafficking to tumor lesions and by the inhibition of their function induced by tumor cells themselves and by the tumor microenvironment. On the other hand, the important role of NK cells has been clearly demonstrated in the therapy of high risk leukemias in the haploidentical hematopoietic stem cell (HSC) transplantation setting. NK cells derived from donor HSC kill leukemic cells residual after the conditioning regimen, thus preventing leukemia relapses. In addition, they also kill residual dendritic cells and T lymphocytes, thus preventing both GvH disease and graft rejection.

Keywords: NK cells; activating NK receptors; acute leukemias; alloreactive NK cells; hematopoietic stem cell transplantation; killer Ig-like receptors; tumor microenvironment.

Figure 1

NK cell-based approaches in the immunotherapy of tumors and leukemias. (A) NK cell function may be greatly hampered by inhibitory factors and/or cytokines produced by tumor cells or cells of the tumor microenvironment (e.g., fibroblasts, F) and by hypoxia that primarily induce down-regulation of activating NK receptors. (B) CD16-mediated antibody dependent cytotoxicity (ADCC) appears to be poorly susceptible to the inhibitory tumor microenvironment. This mechanism may contribute to the positive clinical outcome of patients treated with tumor-specific monoclonal antibodies (mAbs). (C) In the T-depleted haplo-HSCT, KIR⁺ alloreactive NK cells derived from donor HSC (generated after 6–8 weeks) kill leukemia blasts (inducing GvL), DC (preventing GvHD), and T cells (preventing graft rejection) remaining after the conditioning regimen. (D) In haplo-HSCT, early leukemia relapses and severe viral infection may occur during the time interval (6–8 weeks) required for the generation of efficient alloreactive NK cells. The novel approach based on TCR α/β⁺- and B cell-depletion allows the infusion of donor-derived mature alloreactive NK cells and TCR γ/δ⁺ cells together with HSC, thus allowing a better control of leukemia relapses, GvHD, graft rejection, and viral infection/reactivation.