Natural Killer Cells Suppress T Cell-Associated Tumor Immune Evasion

Freeman, Andrew J.; Vervoort, Stephin J.; Ramsbottom, Kelly M.; Kelly, Madison J.; Michie, Jessica; Pijpers, Lizzy; Johnstone, Ricky W.; Kearney, Conor J.; Oliaro, Jane

doi:10.1016/j.celrep.2019.08.017

Cited by 96 publications

(67 citation statements)

References 47 publications

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“…We have shown that interference with the IFN-γ signaling pathway and antigen presentation pathway sensitized leukemia cells for NK-mediated lysis. A recent genome-wide CRISPR screen in mouse B16-F10 melanoma cells revealed a similar role of the IFNGR-JAK-STAT pathway and upregulation of MHC class I in protecting tumor cells from killing by mouse NK cells (27), indicating that this negative feedback might be a universal mechanism for tumor immune evasion. Therefore, blockade of IFN-γ signaling in cancer cells by either neutralizing IFN-γ or blocking IFN-γ receptors might improve immunotherapy using NK cell-dependent anti-cancer responses.…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide CRISPR Screen Reveals Cancer Cell Resistance to NK Cells Induced by NK-Derived IFN-γ

Zhuang

Veltri

2019

Front. Immunol.

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The anti-leukemia activity of NK cells helps prevent relapse during hematopoietic stem cell transplantation (HSCT) in leukemia patients. However, the factors that determine the sensitivity or resistance of leukemia cells in the context of NK-mediated cytotoxicity are not well-established. Here, we performed a genome-wide CRISPR screen in the human chronic-myelogenous-leukemia (CML) cell line K562 to identify genes that regulate the vulnerability of leukemia cells to killing by primary human NK cells. The distribution of guide RNAs (gRNAs) in K562 cells that survived co-incubation with NK cells showed that loss of NCR3LG1, which encodes the ligand of the natural cytotoxicity receptor NKp30, protected K562 cells from killing. In contrast, loss of genes that regulate the antigen-presentation and interferon-γ-signaling pathways increased the vulnerability of K562 cells. The addition of IFN-γ neutralizing antibody increased the susceptibility of K562 cells to NK-mediated killing. Upregulation of MHC class I on K562 cells after co-incubation with NK cells was dependent on IFNGR2. Analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) showed that low IFNGR2 expression in cancer tissues was associated with improved overall survival in acute myeloid leukemia (AML) and Kidney Renal Clear Cell Carcinoma (KIRC) patients. Our results, showing that the upregulation of MHC class I by NK-derived IFN-γ leads to resistance to NK cytotoxicity, suggest that targeting IFN-γ responses might be a promising approach to enhance NK cell anti-cancer efficacy.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide CRISPR Screen Reveals Cancer Cell Resistance to NK Cells Induced by NK-Derived IFN-γ

Zhuang

Veltri

2019

Front. Immunol.

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“…16 In addition, NK cells express a wide repertoire of highly polymorphic germline-encoded activating or inhibitory receptors that recognize distinct target cell ligands ( Figure 1b). 17,18 A number of inhibitory NK cell receptors, such as killer-immunoglobulin like receptors (KIRs) or the (C-type lectin-like) natural killer group 2 molecules NKG2A/B, [18][19][20] bind to canonical and non-canonical HLA proteins, thereby inducing the cytolysis of cells lacking expression of these molecules. This process is called "missing-self" recognition.…”

Section: Regulation Of Cytotoxicity -What Causes the Difference Betwementioning

confidence: 99%

Immunotherapy with NK cells: recent developments in gene modification open up new avenues

et al. 2020

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Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success. However, application-related toxicities, such as cytokine release syndrome or neurotoxicity, moved natural killer (NK) cells into focus as novel players in immunotherapy. CAR-NK cells provide an advantageous dual killingcapacity by CAR-dependent and-independent mechanisms and induce few side effects. While the majority of trials still use CART cells, CAR-NK cell trials are on the rise with 19 ongoing studies worldwide. This review illuminates the current state of research and clinical application of CAR-NK cells, as well as future developmental potential.

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“…Despite of there are robust evidences about the effect of the immunoediting process on cancer cells, these cells also affect NK cells inducing a progressive loss of their cytotoxic capability and IFN-γ secretion [142,143]. In particular, cancer stem cells (CSCs) may play a significant role in this process.…”

Section: Immunoeditingmentioning

confidence: 99%

Mechanisms of Resistance to NK Cell Immunotherapy

Sordo‐Bahamonde

Vitale

Lorenzo‐Herrero

et al. 2020

Cancers

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Immunotherapy has recently been a major breakthrough in cancer treatment. Natural killer (NK) cells are suitable targets for immunotherapy owing to their potent cytotoxic activity that may target cancer cells in a major histocompatibility complex (MHC) and antigen-unrestricted manner. Current therapies targeting NK cells include monoclonal antibodies that promote NK cell antibody-dependent cell-mediated cytotoxicity (ADCC), hematopoietic stem cell transplantation (HSCT), the adoptive transfer of NK cells, the redirection of NK cells using chimeric antigen receptor (CAR)-NK cells and the use of cytokines and immunostimulatory drugs to boost the anti-tumor activity of NK cells. Despite some encouraging clinical results, patients receiving these therapies frequently develop resistance, and a myriad of mechanisms of resistance affecting both the immune system and cancer cells have been reported. A first contributing factor that modulates the efficacy of the NK cell therapy is the genetic profile of the individual, which regulates all aspects of NK cell biology. Additionally, the resistance of cancer cells to apoptosis and the immunoediting of cancer cells, a process that decreases their immunogenicity and promotes immunosuppression, are major determinants of the resistance to NK cell therapy. Consequently, the efficacy of NK cell anti-tumor therapy is specific to each patient and disease. The elucidation of such immunosubversive mechanisms is crucial to developing new procedures and therapeutic strategies to fully harness the anti-tumor potential of NK cells.

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Natural Killer Cells Suppress T Cell-Associated Tumor Immune Evasion

Cited by 96 publications

References 47 publications

Genome-Wide CRISPR Screen Reveals Cancer Cell Resistance to NK Cells Induced by NK-Derived IFN-γ

Genome-Wide CRISPR Screen Reveals Cancer Cell Resistance to NK Cells Induced by NK-Derived IFN-γ

Immunotherapy with NK cells: recent developments in gene modification open up new avenues

Mechanisms of Resistance to NK Cell Immunotherapy

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