NKG2D and MICA/B shedding: a ‘tag game’ between NK cells and malignant cells

Xing, Samantha; Andrade, Lucas Ferrari de

doi:10.1002/cti2.1230

Cited by 78 publications

(62 citation statements)

References 61 publications

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“…In addition, the involvement of MICA/B activation proteins was recently reported to impact on anti-tumor activity of NK cell [ 25 ]. Therefore, the extent of CD95, DR4, DR5, MICA/B expression alterations were then determined after cordycepin treatment for 24 h in either mRNA or protein levels.…”

Section: Resultsmentioning

confidence: 99%

Cordycepin Sensitizes Cholangiocarcinoma Cells to Be Killed by Natural Killer-92 (NK-92) Cells

et al. 2021

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Immunotherapy harnessing immune functions is a promising strategy for cancer treatment. Tumor sensitization is one approach to enhance tumor cell susceptibility to immune cell cytotoxicity that can be used in combination with immunotherapy to achieve therapeutic efficiency. Cordycepin, a bioactive compound that can be extracted from some Cordyceps spp. has been reported to effectively inhibit tumor growth, however, the mechanism of its tumor sensitization activity that enhances immune cell cytotoxicity is unknown. In the present study, we investigated the potency of cordycepin to sensitize a lethal cancer, cholangiocarcinoma (CCA), to natural killer (NK) cells. Treatment with cordycepin prior to and during co-culturing with NK-92 cells significantly increased cell death of KKU-213A as compared to solitary cordycepin or NK treatment. Moreover, sensitization activity was also observed in the combination of NK-92 cells and Cordyceps militaris extract that contained cordycepin as a major component. The cordycepin treatment remarkably caused an increase in TRAIL receptor (DR4 and DR5) expression in KKU-213A, suggesting the possible involvement of TRAIL signaling in KKU-213A sensitization to NK-92 cells. In conclusion, this is the first report on the sensitization activity of cordycepin on CCA cells to NK cytotoxicity, which supports that cordycepin can be further developed as an alternate immunomodulating agent.

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Section: Resultsmentioning

confidence: 99%

Cordycepin Sensitizes Cholangiocarcinoma Cells to Be Killed by Natural Killer-92 (NK-92) Cells

et al. 2021

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“…This degradation causes tumor progression, biological functions, and an immunomodulatory response. Various studies have shown that the shedding of MICA on the surface of tumor cells is increased by proteases, including metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) [42]. For instance, the overexpression of MMP-2 on the surface of renal cell carcinoma and membrane-type MMP-14 activity directly led to MICA shedding [43,44].…”

Section: Discussionmentioning

confidence: 99%

NLRP3 Deficiency in Hepatocellular Carcinoma Enhances Surveillance of NK-92 through a Modulation of MICA/B

Lee

Kim

Jung

et al. 2021

IJMS

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Human hepatocellular carcinoma (HCC) is the most common and even worse at prognosis. The patients with HCC which accompanied by other diseases, such as cirrhosis, can be limited in various treatments, such as chemotherapy, not HCC patients without other diseases. NLRP3 inflammasome plays an important role in the innate immune response, but emerging evidence has indicated that the NLRP3 inflammasome is implicated in all stages of cancer development. Various cells express NLRP3 protein through the autocrine or paracrine signaling in their environment, but NK cells do not. The expanding evidence shows that patients who suffer from liver cancers have a low frequency of natural killer (NK) cells, and the function of these cells is also impaired. Thus, we examined how the expression of NLRP3 in HCC cells affects cancer surveillance by NK cells in a state of a co-culture of both cells. When the expression of NLRP3 in HCC cells was ablated, MICA/B on the surface of HCC cells was upregulated through the lowered expression of matrix metalloproteinase. The expression of MICA on the surface of HCC cells interacted with the NKG2D receptor on NK-92 cells, which led to NK cytotoxicity. Furthermore, in a xenograft mice model, NLRP3 KO HCC cells delayed tumor development and metastasis as well as increased the sensitivity to NK cell cytotoxicity. Taken together, NLRP3 KO in HCC could enhance NK immunosurveillance through an interaction of NKG2D-MICA.

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“…For instance, MHC class I-related chain molecules A and B (MICA and MICB) and natural cytotoxicity triggering receptor 3 ligand 1 (NR3LG1), also referred to B7-H6, are widely expressed by tumor cells (50,51), and they have been reported to be substrates of ADAM17 (52)(53)(54)(55). MICA/B and NR3LG1 are ligands of the NK cell activating receptor NKG2D and NKp30, respectively, and blocking their shedding increased tumor cell killing by NK cells (55,56). The above findings reveal that ADAM17's impact on NK cells is diverse (e.g., effector functions, proliferation, and trafficking) and multifactorial, thus addressing the effects of its inhibition on their function, especially in vivo, is complex.…”

Section: Discussionmentioning

confidence: 99%

Activation of ADAM17 by IL-15 Limits Human NK Cell Proliferation

et al. 2021

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Natural killer (NK) cells are innate cytotoxic lymphocytes that can recognize assorted determinants on tumor cells and rapidly kill these cells. Due to their anti-tumor effector functions and potential for allogeneic use, various NK cell platforms are being examined for adoptive cell therapies. However, their limited in vivo persistence is a current challenge. Cytokine-mediated activation of these cells is under extensive investigation and interleukin-15 (IL-15) is a particular focus since it drives their activation and proliferation. IL-15 efficacy though is limited in part by its induction of regulatory checkpoints. A disintegrin and metalloproteinase-17 (ADAM17) is broadly expressed by leukocytes, including NK cells, and it plays a central role in cleaving cell surface receptors, a process that regulates cell activation and cell-cell interactions. We report that ADAM17 blockade with a monoclonal antibody markedly increased human NK cell proliferation by IL-15 both in vitro and in a xenograft mouse model. Blocking ADAM17 resulted in a significant increase in surface levels of the homing receptor CD62L on proliferating NK cells. We show that NK cell proliferation in vivo by IL-15 and the augmentation of this process upon blocking ADAM17 are dependent on CD62L. Hence, our findings reveal for the first time that ADAM17 activation in NK cells by IL-15 limits their proliferation, presumably functioning as a feedback system, and that its substrate CD62L has a key role in this process in vivo. ADAM17 blockade in combination with IL-15 may provide a new approach to improve NK cell persistence and function in cancer patients.

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NKG2D and MICA/B shedding: a ‘tag game’ between NK cells and malignant cells

Cited by 78 publications

References 61 publications

Cordycepin Sensitizes Cholangiocarcinoma Cells to Be Killed by Natural Killer-92 (NK-92) Cells

Cordycepin Sensitizes Cholangiocarcinoma Cells to Be Killed by Natural Killer-92 (NK-92) Cells

NLRP3 Deficiency in Hepatocellular Carcinoma Enhances Surveillance of NK-92 through a Modulation of MICA/B

Activation of ADAM17 by IL-15 Limits Human NK Cell Proliferation

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