Human NK cells: surface receptors, inhibitory checkpoints, and translational applications

Abstract

NK cells play important roles in innate defenses against viruses and in the control of tumor growth and metastasis. The regulation/induction of NK cell function is mediated by an array of activating or inhibitory surface receptors. In humans, major activating receptors involved in target cell killing are the natural cytotoxicity receptors (NCRs) and NKG2D. Activating receptors recognize ligands that are overexpressed or expressed de novo upon cell stress, viral infection, or tumor transformation. The HLA-class I-specific inhibitory receptors, including KIRs recognizing HLA-class I allotypic determinants and CD94/NKG2A recognizing the class-Ib HLA-E, constitute a fail-safe mechanism to avoid unwanted NK-mediated damage to healthy cells. Other receptors such as PD-1, primarily expressed by activated T lymphocytes, are important inhibitory checkpoints of immune responses that ensure T-cell tolerance. PD-1 also may be expressed by NK cells in cancer patients. Since PD-1 ligand (PD-L1) may be expressed by different tumors, PD-1/PD-L1 interactions inactivate both T and NK cells. Thus, the reliable evaluation of PD-L1 expression in tumors has become a major issue to select patients who may benefit from therapy with mAbs disrupting PD-1/PD-L1 interactions. Recently, NKG2A was revealed to be an important checkpoint controlling both NK and T-cell activation. Since most tumors express HLA-E, mAbs targeting NKG2A has been used alone or in combination with other therapeutic mAbs targeting PD-1 or tumor antigens (e.g., EGFR), with encouraging results. The translational value of NK cells and their receptors is evidenced by the extraordinary therapeutic success of haploidentical HSCT to cure otherwise fatal high-risk leukemias.

Keywords: Human NK cells, NK receptors, Inhibitory checkpoints, Immunotherapy.

Fig. 1

Effects of blocking NKG2A alone or in combination with other therapeutic mAbs disrupting the PD-1/PD-L1 axis or directed to tumor-specific antigens. (1) Cytolytic NK cells expressing the NKG2A inhibitory receptor acquire the ability to kill HLA-E⁺ tumor cells upon mAb-mediated masking of NKG2A. (2) NKG2A⁺ NK cells that also express PD1 are rescued from their anergic state and kill HLA-E⁺ PD-L1⁺ tumor cells upon disruption of the two inhibitory pathways with mAbs specific for NKG2A and PD-L1 (or PD-1), respectively. (3) The therapeutic activity of mAbs directed to tumor-specific antigens (in this case EGFR) is mainly mediated via CD16 (FcγRIII) expressed by highly mature cytolytic NK cells. However, in the case of HLA-E⁺ tumors, the coexpression of NKG2A may represent a major brake on NK-mediated function. Accordingly, masking of NKG2A may restore NK cell function and allow killing of tumor cells targeted by specific mAbs