NK cell‐mediated anti‐leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti‐CD20 scfv chimeric protein

Zou, Yizhou; Luo, Wei; Guo, Jing; Luo, Qizhi; Deng, Mi; Lu, Zhigang; Fang, Yi; Zhang, Cheng Cheng

doi:10.1002/eji.201847550

Cited by 8 publications

(10 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Wan and his team [35] reported that MICA is released into circulation due to shedding of MICA from cell membranes during tumor transformation or upon stress. We showed that sMICA binds to cells expressing the NKG2D receptor but does not activate NKG2D receptor-mediated signaling and does not activate of NK cells [25]. It was previously reported that the binding of sMICA decreases the expression of NKG2D receptor in NK cells [36].…”

Section: Discussionmentioning

confidence: 66%

“…These experiments are used as the well-model to understand how sMICA inhibits the immuno-response of NK and CD8+ T cells to tumor cells. Using microscopy, we previously observed that the single NKG2D dimer is not activated until multiple NKG2D dimers gather into a bundle [25]. This aggregation promotes DAP12 phosphorylation and downstream signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Human fibroblasts cell (HFC), T hybridoma 2B4 cells, and the human NKG2D reporter cells (NKG2D-2B4 cells), which have been prepared as our previous work [25], were cultured in RPMI-1640 medium with 10% FBS at 37 °C in 5% CO2. The NKG2D reporter cells were constructed NKG2D receptor on 2B4 cells containing a nuclear factor of activated T cells (NFAT)-responsive green fluorescent protein (GFP) reporter gene [28].…”

Section: Cells and Cell Culturementioning

confidence: 99%

“…In our previous study, we showed that a fusion protein composed of the MICA extracellular domain (MICA-ECD) and an anti-CD20 single-chain antibody (ScFv) induced NK cell-mediated killing of CD20 + tumor cells [25]. NKG2D and its ligands are involved in the development of prostate cancer, leukemia, melanoma, and other tumors [26].…”

mentioning

confidence: 99%

See 3 more Smart Citations

Tumor-Derived Soluble MICA Obstructs the NKG2D Pathway to Restrain NK Cytotoxicity

Luo¹,

Luo²,

Zhu³

et al. 2020

Aging and disease

View full text Add to dashboard Cite

The natural killer group 2D (NKG2D) receptor and its ligands play important roles in immune surveillance. In this study, we observed that the average serum soluble MICA (sMICA) concentration of 174 hepatocellular carcinoma (HCC) patients was significantly higher than that in 80 healthy subjects (602.17 ± 338.15 vs. 72.26 ± 87.88 pg/ml, t = 3.107, P=0.002). The levels of serum sMICA in 44 HCC patients with initial levels above 400 pg/ml declined significantly after surgical removal of the liver cancer tissue (P<0.001). Moreover, the mean survival time of HCC patients who had sMICA above 400 pg/ml was significantly shorter than that HCC patients with lower sMICA levels (P<0.001). Using the reporter cell line (NKG2D-2B4) in which activation of the NKG2D receptor pathway results in GFP expression based on the stimulation of immobilized rMICA, we showed that the number of GFP-expressing cells decreased sharply in presence of sMICA. Upon adding sMICA, the release of cytokines IFN-γ, TNF-α, and IL-8 by NK cell line (NKL) under stimulation of immobilized rMICA was blocked. Using MICA-expressing cells as the target cells, we observed that about 80% of target cells were killed by NKL at E:T of 10:1, but in presence of sMICA high serum of HCC patients, the dead target cells were reduced to 30.8%. Compared in presence of sMICA low serum from HCC patients, there were 63.7% of target cells dead (p=0.043). Thus, our data suggested that sMICA obstructs the activation of NKG2D pathway to protect tumor cells from NK cell-mediated cytotoxicity.

show abstract

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Cells and Cell Culturementioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Tumor-Derived Soluble MICA Obstructs the NKG2D Pathway to Restrain NK Cytotoxicity

Luo¹,

Luo²,

Zhu³

et al. 2020

Aging and disease

View full text Add to dashboard Cite

show abstract

“…NKL cells were cultured as previously described. 19 All cell culture medium were supplemented with 1% penicillin and streptomycin.…”

Section: Cell Lines and Primary Samplesmentioning

confidence: 99%

Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells

Chen

Deng

et al. 2020

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

BackgroundCurrent immune checkpoint blockade strategies have been successful in treating certain types of solid cancer. However, checkpoint blockade monotherapies have not been successful against most hematological malignancies including multiple myeloma and leukemia. There is an urgent need to identify new targets for development of cancer immunotherapy. LILRB1, an immunoreceptor tyrosine-based inhibitory motif-containing receptor, is widely expressed on human immune cells, including B cells, monocytes and macrophages, dendritic cells and subsets of natural killer (NK) cells and T cells. The ligands of LILRB1, such as major histocompatibility complex (MHC) class I molecules, activate LILRB1 and transduce a suppressive signal, which inhibits the immune responses. However, it is not clear whether LILRB1 blockade can be effectively used for cancer treatment.MethodsFirst, we measured the LILRB1 expression on NK cells from cancer patients to determine whether LILRB1 upregulated on NK cells from patients with cancer, compared with NK cells from healthy donors. Then, we developed specific antagonistic anti-LILRB1 monoclonal antibodies and studied the effects of LILRB1 blockade on the antitumor immune function of NK cells, especially in multiple myeloma models, in vitro and in vivo xenograft model using non-obese diabetic (NOD)-SCID interleukin-2Rγ-null mice.ResultsWe demonstrate that percentage of LILRB1+ NK cells is significantly higher in patients with persistent multiple myeloma after treatment than that in healthy donors. Further, the percentage of LILRB1+ NK cells is also significantly higher in patients with late-stage prostate cancer than that in healthy donors. Significantly, we showed that LILRB1 blockade by our antagonistic LILRB1 antibody increased the tumoricidal activity of NK cells against several types of cancer cells, including multiple myeloma, leukemia, lymphoma and solid tumors, in vitro and in vivo.ConclusionsOur results indicate that blocking LILRB1 signaling on immune effector cells such as NK cells may represent a novel strategy for the development of anticancer immunotherapy.

show abstract

NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity

Herault,

Mak,

de la Cruz-Chuh

et al. 2024

Cancer Immunol Immunother

View full text Add to dashboard Cite

Background Cancer immunotherapy approaches that elicit immune cell responses, including T and NK cells, have revolutionized the field of oncology. However, immunosuppressive mechanisms restrain immune cell activation within solid tumors so additional strategies to augment activity are required. Methods We identified the co-stimulatory receptor NKG2D as a target based on its expression on a large proportion of CD8+ tumor infiltrating lymphocytes (TILs) from breast cancer patient samples. Human and murine surrogate NKG2D co-stimulatory receptor-bispecifics (CRB) that bind NKG2D on NK and CD8+ T cells as well as HER2 on breast cancer cells (HER2-CRB) were developed as a proof of concept for targeting this signaling axis in vitro and in vivo. Results HER2-CRB enhanced NK cell activation and cytokine production when co-cultured with HER2 expressing breast cancer cell lines. HER2-CRB when combined with a T cell-dependent-bispecific (TDB) antibody that synthetically activates T cells by crosslinking CD3 to HER2 (HER2-TDB), enhanced T cell cytotoxicity, cytokine production and in vivo antitumor activity. A mouse surrogate HER2-CRB (mHER2-CRB) improved in vivo efficacy of HER2-TDB and augmented NK as well as T cell activation, cytokine production and effector CD8+ T cell differentiation. Conclusion We demonstrate that targeting NKG2D with bispecific antibodies (BsAbs) is an effective approach to augment NK and CD8+ T cell antitumor immune responses. Given the large number of ongoing clinical trials leveraging NK and T cells for cancer immunotherapy, NKG2D-bispecifics have broad combinatorial potential. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-024-03795-2.

show abstract

NK cell‐mediated anti‐leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti‐CD20 scfv chimeric protein

Cited by 8 publications

References 56 publications

Tumor-Derived Soluble MICA Obstructs the NKG2D Pathway to Restrain NK Cytotoxicity

Tumor-Derived Soluble MICA Obstructs the NKG2D Pathway to Restrain NK Cytotoxicity

Antagonistic anti-LILRB1 monoclonal antibody regulates antitumor functions of natural killer cells

NKG2D-bispecific enhances NK and CD8+ T cell antitumor immunity

Contact Info

Product

Resources

About