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20.12.2017 | Focussed Research Review | Ausgabe 12/2018

Cancer Immunology, Immunotherapy 12/2018

Splice variants of human natural cytotoxicity receptors: novel innate immune checkpoints

Cancer Immunology, Immunotherapy > Ausgabe 12/2018
Avishai Shemesh, Michael Brusilovsky, Kiran Kundu, Aner Ottolenghi, Kerry S. Campbell, Angel Porgador
Wichtige Hinweise
This paper is a Focussed Research Review based on a presentation given at the Fifth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2017), held in Prague, Czech Republic, 24th–27th April 2017. It is part of a series of Focussed Research Reviews and meeting report in Cancer Immunology, Immunotherapy.


The natural cytotoxicity receptors (NCRs; NKp30, NKp44, and NKp46) were first defined as activating receptors on human NK cells that are important in recognition of and response to tumors. A flurry of recent research, however, has revealed that differential splicing can occur during transcription of each of the NCR genes, resulting in some transcripts that encode receptor isoforms with inhibitory functions. These alternative transcripts can arise in certain tissue microenvironments and appear to be induced by cytokines. Evidence indicates that some of the inhibitory NCRs are triggered by specific ligands, such as the interaction of the inhibitory isoform of NKp44 with PCNA on the surface of tumor cells. Here, we review the different NCR splice variants, cytokines that modulate their expression, their functional impacts on innate immune cells, and their differential expression in the contexts of cancer, pregnancy, and infections. The recent discovery of these inhibitory NCR isoforms has revealed novel innate immune checkpoints, many of which still lack defined ligands and clear mechanisms driving their expression. These NCR checkpoint pathways offer exciting potential therapeutic targets to manipulate innate immune functions under defined pathological conditions, such as cancer, pregnancy disorders, and pathogen exposure.

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