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

Simona Sivori, Mariella Della Chiesa, Simona Carlomagno, Linda Quatrini, Enrico Munari, Paola Vacca, Nicola Tumino, Francesca Romana Mariotti, Maria Cristina Mingari, Daniela Pende, Lorenzo Moretta

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish
Article number2156
JournalFrontiers in Immunology
Publication statusPublished - Sept 3 2020


  • immune checkpoints
  • inhibitory NK receptors
  • natural killer cells
  • tumor escape
  • tumor immunotherapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


Dive into the research topics of 'Inhibitory Receptors and Checkpoints in Human NK Cells, Implications for the Immunotherapy of Cancer'. Together they form a unique fingerprint.

Cite this