Minimal PD-1 expression in mouse and human NK cells under diverse conditions

Judge, Sean J; Dunai, Cordelia; Aguilar, Ethan G.; Vick, Sarah C.; Sturgill, Ian R.; Khuat, Lam T.; Stoffel, Karl; Dyke, Jonathan Van; Longo, Dan L.; Darrow, Morgan A.; Anderson, Stephen; Blazar, Bruce R.; Monjazeb, Arta M.; Serody, Jonathan S.; Canter, Robert J.; Murphy, William J.

doi:10.1172/jci133353

Cited by 110 publications

(99 citation statements)

References 69 publications

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“…Human peripheral blood mononuclear cells (PBMCs) were isolated from whole blood using a density gradient centrifugation (Lymphocyte Separation Medium, Corning Life Sciences), followed by red blood cell lysis, as described previously. 24 Preparation of human STS tumors Tumor tissue from patients undergoing STS resection was collected in sterile RPMI-1640 (Invitrogen Life Technologies), diluted with phosphate-buffered saline (PBS) and passed through a 70 µm filter, and then subjected to red blood cell lysis. Cells were either plated for in vitro assays or analyzed by flow cytometry as described below.…”

Section: Preparation Of Human Peripheral Blood Mononuclear Cellsmentioning

confidence: 99%

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas

Judge

Darrow

Thorpe

et al. 2020

J Immunother Cancer

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PurposeGiven the unmet need for novel immunotherapy in soft tissue sarcoma (STS), we sought to characterize the phenotype and function of intratumoral natural killer (NK) and T cells to identify novel strategies to augment tumor-infiltrating lymphocyte (TIL) function.Experimental designUsing prospectively collected specimens from dogs and humans with sarcomas, archived specimens, and The Cancer Genome Atlas (TCGA) data, we evaluated blood and tumor NK and T cell phenotype and function and correlated those with outcome. We then assessed the effects of interleukin 15 (IL-15) stimulation on both NK and T cell activation and TIGIT upregulation. Finally, we evaluated cytotoxic effects of IL-15 combined with TIGIT blockade using a novel anti-TIGIT antibody.ResultsTILs were strongly associated with survival outcome in both archived tissue and TCGA, but higher TIL content was also associated with higher TIGIT expression. Compared with blood, intratumoral NK and T cells showed significantly higher expression of both activation and exhaustion markers, in particular TIGIT. Ex vivo stimulation of blood and tumor NK and T cells from patients with STS with IL-15 further increased both activation and exhaustion markers, including TIGIT. Dogs with metastatic osteosarcoma receiving inhaled IL-15 also exhibited upregulation of activation markers and TIGIT. Ex vivo, combined IL-15 and TIGIT blockade using STS blood and tumor specimens significantly increased cytotoxicity against STS targets.ConclusionIntratumoral NK and T cells are prognostic in STS, but their activation is marked by significant upregulation of TIGIT. Our data suggest that combined IL-15 and TIGIT blockade may be a promising clinical strategy in STS.

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Section: Preparation Of Human Peripheral Blood Mononuclear Cellsmentioning

confidence: 99%

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas

Judge

Darrow

Thorpe

et al. 2020

J Immunother Cancer

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“…In a recent report, Judge and colleagues [63] failed to reproduce the results of other groups as they could not show PD-1 expression on NK cells in viral and tumour models [63]. The authors checked PD-1 expression on murine, canine and human NK cells in parallel with other activation and exhaustion markers using multiple techniques, including flow cytometry, quantitative real-time PCR and RNA sequencing.…”

Section: Evidence For Pd-1 and Pd-l1 Expression On Nk Cellsmentioning

confidence: 99%

“…The authors checked PD-1 expression on murine, canine and human NK cells in parallel with other activation and exhaustion markers using multiple techniques, including flow cytometry, quantitative real-time PCR and RNA sequencing. They repeatedly demonstrated that NK cells in many solid tumour murine models and in MCMV infection, and human NK cells activated in vitro and isolated from cancer patients' samples, all display minimal PD-1 expression [63]. Therefore, they concluded that, because of the minimal PD-1 expression on NK cells, their contribution to immunotherapy may not be significant and PD-1/PD-L1 pathway does not contribute to NK cell immunoregulation.…”

Section: Evidence For Pd-1 and Pd-l1 Expression On Nk Cellsmentioning

confidence: 99%

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

Quatrini

Mariotti

Munari

et al. 2020

Cancers

110

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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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“…Some studies suggest that PD-1 is expressed solely on activated NK cells [111], while others have identified PD-1 expression as a marker for dysfunctional or exhausted NK cells [112][113][114]. Most recently, Judge et al [115] compared PD-1 expression on mouse, humanand canine, T cells and NK cells under various conditions in vitro and investigated intratumoral NK cells in sarcoma, colon cancer, and head and neck squamous carcinoma, concluding that PD-1 was not significantly expressed on mouse or human NK cells. However, there may still be an argument for combining anti-PD-1 therapy with other checkpoint blockers to rescue exhausted NK cells [114].…”

Section: Non-mhc-i Recognizing Receptorsmentioning

confidence: 99%

Natural Killer Cells: Tumor Surveillance and Signaling

Guzman

Keating

Nicholson

2020

Cancers

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Natural killer (NK) cells play a pivotal role in cancer immunotherapy due to their innate ability to detect and kill tumorigenic cells. The decision to kill is determined by the expression of a myriad of activating and inhibitory receptors on the NK cell surface. Cell-to-cell engagement results in either self-tolerance or a cytotoxic response, governed by a fine balance between the signaling cascades downstream of the activating and inhibitory receptors. To evade a cytotoxic immune response, tumor cells can modulate the surface expression of receptor ligands and additionally, alter the conditions in the tumor microenvironment (TME), tilting the scales toward a suppressed cytotoxic NK response. To fully harness the killing power of NK cells for clinical benefit, we need to understand what defines the threshold for activation and what is required to break tolerance. This review will focus on the intracellular signaling pathways activated or suppressed in NK cells and the roles signaling intermediates play during an NK cytotoxic response.

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Minimal PD-1 expression in mouse and human NK cells under diverse conditions

Cited by 110 publications

References 69 publications

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas

Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas

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

Natural Killer Cells: Tumor Surveillance and Signaling

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