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Review
. 2019 Jun 4:10:1242.
doi: 10.3389/fimmu.2019.01242. eCollection 2019.

PD/1-PD-Ls Checkpoint: Insight on the Potential Role of NK Cells

Silvia Pesce  1 , Marco Greppi  1   2 , Francesco Grossi  3 , Genny Del Zotto  4 , Lorenzo Moretta  5 , Simona Sivori  1   2 , Carlo Genova  6 , Emanuela Marcenaro  1   2
Affiliations
Review

PD/1-PD-Ls Checkpoint: Insight on the Potential Role of NK Cells

Silvia Pesce et al. Front Immunol. .

Abstract

The identification of inhibitory NK cell receptors specific for HLA-I molecules (KIRs and NKG2A) provided the molecular basis for clarifying the mechanism by which NK cells kill transformed cells while sparing normal cells. The direct interactions between inhibitory NK cell receptors and their HLA-I ligands enable NK cells to distinguish healthy from transformed cells, which frequently show an altered expression of HLA-I molecules. Indeed, NK cells can kill cancer cells that have lost, or under express, HLA-I molecules, but not cells maintaining their expression. In this last case, it is possible to use anti-KIR or anti-NKG2A monoclonal antibodies to block the inhibitory signals generated by these receptors and to restore the anti-tumor NK cell activity. These treatments fall within the context of the new immunotherapeutic strategies known as "immune checkpoint blockade." These antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. However, a more complex scenario has recently emerged. For example, NK cells can also express additional immune checkpoints, including PD-1, that was originally described on T lymphocytes, and whose ligands (PD-Ls) are usually overexpressed on tumor cells. Thus, it appears that the activation of NK cells and their potentially harmful effector functions are under the control of different immune checkpoints and their simultaneous expression could provide additional levels of suppression to anti-tumor NK cell responses. This review is focused on PD-1 immune checkpoint in NK cells, its potential role in immunosuppression, and the therapeutic strategies to recover NK cell cytotoxicity and anti-tumor effect.

Keywords: KIR; NK cells; NKG2A; PD-1; PD-L; immune checkpoint; immune checkpoint blockade; immunotherapy.

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Figures

Figure 1
Figure 1
New insight on the potential role of PD-1 in NK cells and in other ILCs.
See this image and copyright information in PMC

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References

    1. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. (1995) 3:541–7. 10.1016/1074-7613(95)90125-6 - DOI - PubMed
    1. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. (1999) 11:141–51. 10.1016/S1074-7613(00)80089-8 - DOI - PubMed
    1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. (2012) 12:252–64. 10.1038/nrc3239 - DOI - PMC - PubMed
    1. Ledford H. Melanoma drug wins US approval. Nature. (2011) 471:561. 10.1038/471561a - DOI - PubMed
    1. Sharma P, Wagner K, Wolchok JD, Allison JP. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat Rev Cancer. (2011) 11:805–12. 10.1038/nrc3153 - DOI - PMC - PubMed

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