Inhibitory checkpoints in human natural killer cells: IUPHAR Review 28

Mariotti, Francesca Romana; Quatrini, Linda; Munari, Enrico; Vacca, Paola; Tumino, Nicola; Pietra, Gabriella; Mingari, Maria Cristina; Moretta, Alessandro

doi:10.1111/bph.15081

Cited by 11 publications

(10 citation statements)

References 151 publications

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“…The efficacy of PD-1/PD-L1 axis blockade in HLA I − tumours [45], together with the finding that triggering PD-L1 on NK cells with anti-PD-L1 mAbs enhances anti-tumor response [71], suggests a relevant contribution of NK cells in the positive outcome of therapies targeting either the receptor or the ligand. Moreover, given the similar profiles of surface inhibitory receptors expression by T and NK cells, a promising strategy consists in the utilization of combined immunotherapies targeting multiple checkpoints besides the PD-1/PD-L1 axis, including NKG2A, TIM-3, LAG-3 and TIGIT [8]. It is expected that the number of therapies involving, but not limited to, the inhibition of the PD-1/PD-L1 axis will continue to rise, together with their clinical indications.…”

Section: Targeting the Pd-1/pd-l1mentioning

confidence: 99%

“…Moreover, impaired NK cell function in the TME has been associated with the increased expression of inhibitory receptors. Among these, a number of receptors have been identified and studied, which do not bind HLA class I molecules, but instead ligands expressed by tumour cells, favouring a mechanism of evasion from immune recognition [8]. These inhibitory receptors include Programmed cell death protein 1 (PD-1), Lymphocyte Activation Gene 3 (LAG3), T cell immunoglobulin and mucin-domain containing-3 (TIM3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT).…”

Section: Introductionmentioning

confidence: 99%

“…As surface molecules, immune checkpoints' activity can be inhibited by blocking antibodies that prevent ligand-receptor engagement. The most successful immune checkpoint blockade therapy to date is anti-PD-1/PD-L1 therapy, currently approved to treat a wide variety of cancer types [8]. While it was initially thought that blocking PD-1/PD-L1 axis would only unleash T cell response, it is now becoming clear that NK cell responses may also be potentiated through this strategy.…”

Section: Introductionmentioning

confidence: 99%

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The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

Quatrini

Mariotti

Munari

et al. 2020

Cancers

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In the last years, immunotherapy with antibodies against programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has shown remarkable efficacy in the treatment of different types of tumours, representing a true revolution in oncology. While its efficacy has initially been attributed only to unleashing T cell responses, responsivity to PD-1/PD-L1 blockade was observed in some tumours with low Human Leukocyte Antigen (HLA) I expression and increasing evidence has revealed PD-1 surface expression and inhibitory function also in natural killer (NK) cells. Thus, the contribution of anti-PD-1/PD-L1 therapy to the recovery of NK cell anti-tumour response has recently been appreciated. Here, we summarize the studies investigating PD-1 expression and function in NK cells, together with the limitations and perspectives of immunotherapies. A better understanding of checkpoint biology is needed to design next-generation therapeutic strategies and to improve the clinical protocols of current therapies.

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Section: Targeting the Pd-1/pd-l1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

Quatrini

Mariotti

Munari

et al. 2020

Cancers

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“…Accordingly, PD-1 deficiency is associated with the development of autoimmune diseases (11,12). PD-1 can be expressed also by γδ T cells, natural killer (NK) cells, and innate lymphoid cells (ILCs), which are circulating and tissue-resident lymphocytes involved in tissue repair and early responses against pathogens and cellular stress (13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Regulation of PD-L1 Expression by NF-κB in Cancer

et al. 2020

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Immune checkpoints are inhibitory receptor/ligand pairs regulating immunity that are exploited as key targets of anti-cancer therapy. Although the PD-1/PD-L1 pair is one of the most studied immune checkpoints, several aspects of its biology remain to be clarified. It has been established that PD-1 is an inhibitory receptor up-regulated by activated T, B, and NK lymphocytes and that its ligand PD-L1 mediates a negative feedback of lymphocyte activation, contributing to the restoration of the steady state condition after acute immune responses. This loop might become detrimental in the presence of either a chronic infection or a growing tumor. PD-L1 expression in tumors is currently used as a biomarker to orient therapeutic decisions; nevertheless, our knowledge about the regulation of PD-L1 expression is limited. The present review discusses how NF-κB, a master transcription factor of inflammation and immunity, is emerging as a key positive regulator of PD-L1 expression in cancer. NF-κB directly induces PD-L1 gene transcription by binding to its promoter, and it can also regulate PD-L1 post-transcriptionally through indirect pathways. These processes, which under conditions of cellular stress and acute inflammation drive tissue homeostasis and promote tissue healing, are largely dysregulated in tumors. Up-regulation of PD-L1 in cancer cells is controlled via NF-κB downstream of several signals, including oncogene- and stress-induced pathways, inflammatory cytokines, and chemotherapeutic drugs. Notably, a shared signaling pathway in epithelial cancers induces both PD-L1 expression and epithelial–mesenchymal transition, suggesting that PD-L1 is part of the tissue remodeling program. Furthermore, PD-L1 expression by tumor infiltrating myeloid cells can contribute to the immune suppressive features of the tumor environment. A better understanding of the interplay between NF-κB signaling and PD-L1 expression is highly relevant to cancer biology and therapy.

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“…Blockade of the PD-1/PD-L1 axis through monoclonal antibodies represents a major breakthrough in oncology, showing significant clinical success in the treatment of several types of cancers (70,71). This blockade allows unleashing not only T cell-, but also NK cell-mediated anti-tumor response.…”

Section: Pd-1mentioning

confidence: 99%

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

et al. 2020

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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.

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Inhibitory checkpoints in human natural killer cells: IUPHAR Review 28

Cited by 11 publications

References 151 publications

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

Regulation of PD-L1 Expression by NF-κB in Cancer

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

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