Generation and Preclinical Characterization of an NKp80-Fc Fusion Protein for Redirected Cytolysis of Natural Killer (NK) Cells against Leukemia

Deng, Gang; Zheng, Xiaodong; Zhou, Jing; Wei, Haiming; Tian, Zhigang; Sun, Rui

doi:10.1074/jbc.m115.678912

Cited by 11 publications

(7 citation statements)

References 22 publications

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“…In our study, the NKMS was composed of 7 NK cell marker ( CLEC2B , PLAC8 , CD7 , SH3BGRL3 , CALM1 , KLRF1 , and JAK1 ), which were all reported to be involved in the oncogenesis. CLEC2B , also known as activation-induced C-type lectin ( AICL ), is an identified ligand for NK-activating receptor KLRF1 (previously called NKp80 ) and is of importance in NK cell activation and regulation ( 41 , 42 ). PLAC8 is a small 12.5 kDa protein and has been reported to function in death of human lymphocytes, adipocyte differentiation and human diseases, including cancer ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis of single-cell and bulk transcriptome identifies a signature based on NK cell marker genes to predict prognosis and therapeutic response in clear cell renal cell carcinoma

Wang¹,

Yu²,

Zhang³

et al. 2023

Transl Cancer Res

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Background: Accumulating evidence has highlighted the effects of natural killer (NK) cells on shaping anti-tumor immunity. This study aimed to construct an NK cell marker gene signature (NKMS) to predict prognosis and therapeutic response of clear cell renal cell carcinoma (ccRCC) patients.Methods: Publicly available single-cell and bulk RNA profiles with matched clinical information of ccRCC patients were collected from Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), ArrayExpress, and International Cancer Genome Consortium (ICGC) databases. A novel NKMS was constructed, and its prognostic value, associated immunogenomic features and predictive capability to immune checkpoint inhibitors (ICIs) and anti-angiogenic therapies were evaluated in ccRCC patients. Results:We identified 52 NK cell marker genes by single-cell RNA-sequencing (scRNA-seq) analysis in GSE152938 and GSE159115. After least absolute shrinkage and selection operator (LASSO) and Cox regression, the most prognostic 7 genes (CLEC2B, PLAC8, CD7, SH3BGRL3, CALM1, KLRF1, and JAK1) composed NKMS using bulk transcriptome from TCGA. Survival and time-dependent receiver operating characteristic (ROC) analysis exhibited exceptional predictive capability of the signature in the training set and two independent validation cohorts (E-MTAB-1980 and RECA-EU cohorts). The seven-gene signature was able to identify patients within high Fuhrman grade (G3-G4) and American Joint Committee on Cancer (AJCC) stage (III-IV). Multivariate analysis confirmed the independent prognostic value of the signature, and a nomogram was built for clinical utility. The high-risk group was characterized by a higher tumor mutation burden (TMB) and greater infiltration of immunocytes, particularly CD8 + T cells, regulatory T (Treg) cells and follicular helper T (Tfh) cells, in parallel with higher expression of genes negatively regulating anti-tumor immunity. Moreover, high-risk tumors exhibited higher richness and diversity of T-cell receptor (TCR) repertoire. In two therapy cohorts of ccRCC patients (PMID32472114 and E-MTAB-3267), we demonstrated that high-risk group showed greater sensitivity to ICIs, whereas the low-risk group was more likely to benefit from anti-angiogenic therapy.Conclusions: We identified a novel signature that can be utilized as an independent predictive biomarker and a tool for selecting the individualized treatment for ccRCC patients.

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Section: Discussionmentioning

confidence: 99%

Integrated analysis of single-cell and bulk transcriptome identifies a signature based on NK cell marker genes to predict prognosis and therapeutic response in clear cell renal cell carcinoma

Wang¹,

Yu²,

Zhang³

et al. 2023

Transl Cancer Res

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“…Other antibodies targeting TNF family members on AML cells, such as glucocorticoid-induced TNFR-related protein ligand (GITRL) and receptor activator for NF-κB ligand (RANKL), were manifested against primary AML cells in preclinical studies through the prevention of inhibitory signals into NK cells as well as the induction of ADCC [156][157][158]. Despite the inevitable reduction in activating signals upon antibodies binding to ligands of activating receptors, NKG2D-Fc and NKp80-Fc fusion proteins were shown to be able to compensate for it by inducing ADCC to potentiate NK cell killing of AML cells [159,160].…”

Section: Antibodies Targeting Tumor-associated Antigensmentioning

confidence: 99%

Natural killer cell-based immunotherapy for acute myeloid leukemia

Niu

2020

J Hematol Oncol

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Despite considerable progress has been achieved in the treatment of acute myeloid leukemia over the past decades, relapse remains a major problem. Novel therapeutic options aimed at attaining minimal residual disease-negative complete remission are expected to reduce the incidence of relapse and prolong survival. Natural killer cell-based immunotherapy is put forward as an option to tackle the unmet clinical needs. There have been an increasing number of therapeutic dimensions ranging from adoptive NK cell transfer, chimeric antigen receptor-modified NK cells, antibodies, cytokines to immunomodulatory drugs. In this review, we will summarize different forms of NK cell-based immunotherapy for AML based on preclinical investigations and clinical trials.

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“…Eliciting the FcγRIII (CD16) response can allow NK cells to maintain their killing capability through alternate approach of antibody‐dependent cell cytotoxicity (ADCC) . In mice, a shed form of MULT1, a high‐affinity NKG2D ligand, causes NK cell activation and tumor rejection . In neuroblastoma cells, NK cells can contribute to antitumor effects by prompting the MHC‐I up regulation hence playing an important role in tumor eradication.…”

Section: Innate and Adaptive Immune Responses During Tumorigenesismentioning

confidence: 99%

“…32 In mice, a shed form of MULT1, a high-affinity NKG2D ligand, causes NK cell activation and tumor rejection. 33 In neuroblastoma cells, NK cells can contribute to antitumor effects by prompting the MHC-I up regulation 34 hence playing an important role in tumor eradication. Two other subsets of NK cells-CD56 dim CD16 + and CD56 bright CD16 low cells, often present in peripheral blood stream, display high and low cytotoxic effects, respectively.…”

Section: Natural Killer Cellsmentioning

confidence: 99%

Role of immune system in tumor progression and carcinogenesis

Upadhyay

Sharma

Gupta

et al. 2018

J of Cellular Biochemistry

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Tumor micro-environment has potential to customize the behavior of the immune cell according to their need. In immune-eliminating phase, immune cells eliminate transformed cells but after tumor establishment innate and adaptive immune cells synergistically provide shelter as well as fulfill their requirement that helps in progression. In between eliminating and establishment phase, equilibrium and escaping phase regulate the immune cells response. During immune-escaping, (1) the antigenic response generated is either inadequate, or focused entirely on tolerance, and (2) immune response generated is specific and effective, but the tumor skips immune recognition. In this review, we are discussing the critical role of immune cells and their cytokines before and after the establishment of tumor which might play a critical role during immunotherapy.

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Generation and Preclinical Characterization of an NKp80-Fc Fusion Protein for Redirected Cytolysis of Natural Killer (NK) Cells against Leukemia

Cited by 11 publications

References 22 publications

Integrated analysis of single-cell and bulk transcriptome identifies a signature based on NK cell marker genes to predict prognosis and therapeutic response in clear cell renal cell carcinoma

Integrated analysis of single-cell and bulk transcriptome identifies a signature based on NK cell marker genes to predict prognosis and therapeutic response in clear cell renal cell carcinoma

Natural killer cell-based immunotherapy for acute myeloid leukemia

Role of immune system in tumor progression and carcinogenesis

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