Natural Killer Cells in Cancer Immunotherapy

Miller, Jeffrey S.; Lanier, Lewis L.

doi:10.1146/annurev-cancerbio-030518-055653

Cited by 125 publications

(115 citation statements)

References 204 publications

(204 reference statements)

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“…Therefore, CD16-directed bispecific (eg, CD16 and CD19) or trispecific (eg, CD16 and two tumor antigens CD19 and CD22 or one tumor antigen and an IL-15 linker) antibodies or scFv have been developed. 37 Although primarily functioning as innate immune cells, studies have shown that NK cells might also have a role in antigen-specific immunological memory. In a Rag2-deficient model of hapten-induced contact hypersensitivity, NK cell-mediated hapten-specific response was detected for at least a month after priming.…”

Section: Introductionmentioning

confidence: 99%

Lifting the innate immune barriers to antitumor immunity

Rothlin

Ghosh

2020

J Immunother Cancer

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The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors.

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Section: Introductionmentioning

confidence: 99%

Lifting the innate immune barriers to antitumor immunity

Rothlin

Ghosh

2020

J Immunother Cancer

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“…As an alternative to BiTEs, NK-targeting bi-(BiKEs) and tri-specific killer engagers (TriKEs) have been developed [78]. These are composed of small molecules containing the variable portion (V H and V L ) of an antibody linked to one (BiKE) or two (TriKE) variable portions from other antibodies of different specificity.…”

Section: Recent Findings Related To Immunotherapy Against Multiple Mymentioning

confidence: 99%

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

Shimizu

Iyoda

Yamasaki

et al. 2020

Cancers

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Recent cancer treatment modalities have been intensively focused on immunotherapy. The success of chimeric antigen receptor T cell therapy for treatment of refractory B cell acute lymphoblastic leukemia has pushed forward research on hematological malignancies. Among the effector types of innate lymphocytes, natural killer (NK) cells show great importance in immune surveillance against infectious and tumor diseases. Particularly, the role of NK cells has been argued in either elimination of target tumor cells or escape of tumor cells from immune surveillance. Therefore, an NK cell activation approach has been explored. Recent findings demonstrate that invariant natural killer T (iNKT) cells capable of producing IFN-γ when optimally activated can promptly trigger NK cells. Here, we review the role of NKT and/or NK cells and their interaction in anti-tumor responses by highlighting how innate immune cells recognize tumors, exert effector functions, and amplify adaptive immune responses. In addition, we discuss these innate lymphocytes in hematological disorders, particularly multiple myeloma and acute myeloid leukemia. The immune balance at different stages of both diseases is explored in light of disease progression. Various types of innate immunity-mediated therapeutic approaches, recent advances in clinical immunotherapies, and iNKT-mediated cancer immunotherapy as next-generation immunotherapy are then discussed.

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“…Although NK cells can recognize a broad range of cancer cells in vitro, the contribution of their activity to immunotherapy for solid tumors has just begun to be appreciated (5,6). Pre-clinical data have shown that NK cell depletion increases tumor growth (7).…”

Section: Introductionmentioning

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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Natural Killer Cells in Cancer Immunotherapy

Cited by 125 publications

References 204 publications

Lifting the innate immune barriers to antitumor immunity

Lifting the innate immune barriers to antitumor immunity

NK and NKT Cell-Mediated Immune Surveillance against Hematological Malignancies

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

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