Inhibitory Receptors and Checkpoints in Human NK Cells, Implications for the Immunotherapy of Cancer

Front Immunol. 2020 Sep 3:11:2156. doi: 10.3389/fimmu.2020.02156. eCollection 2020.


The highly destructive mechanisms by which the immune system faces microbial infections is under the control of a series of inhibitory receptors. While most of these receptors prevent unwanted/excessive responses of individual effector cells, others play a more general role in immunity, acting as true inhibitory checkpoints controlling both innate and adaptive immunity. Regarding human NK cells, their function is finely regulated by HLA-class I-specific inhibitory receptors which allow discrimination between HLA-I+, healthy cells and tumor or virus-infected cells displaying loss or substantial alterations of HLA-I molecules, including allelic losses that are sensed by KIRs. A number of non-HLA-specific receptors have been identified which recognize cell surface or extracellular matrix ligands and may contribute to the physiologic control of immune responses and tolerance. Among these receptors, Siglec 7 (p75/AIRM-1), LAIR-1 and IRp60, recognize ligands including sialic acids, extracellular matrix/collagen or aminophospholipids, respectively. These ligands may be expressed at the surface of tumor cells, thus inhibiting NK cell function. Expression of the PD-1 checkpoint by NK cells requires particular cytokines (IL-15, IL-12, IL-18) together with cortisol, a combination that may occur in the microenvironment of different tumors. Blocking of single or combinations of inhibitory receptors unleashes NK cells and restore their anti-tumor activity, with obvious implications for tumor immunotherapy.

Keywords: immune checkpoints; inhibitory NK receptors; natural killer cells; tumor escape; tumor immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immune Checkpoint Proteins / metabolism*
  • Immunotherapy, Adoptive / methods*
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / transplantation
  • Lectins / metabolism
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, KIR / metabolism
  • Tumor Escape
  • Tumor Microenvironment


  • Antigens, Differentiation, Myelomonocytic
  • Immune Checkpoint Proteins
  • Lectins
  • Receptors, KIR
  • SIGLEC7 protein, human