Wu, Xiaolong: Promotion of antitumor activity of CIK cells by targeting the NKG2D axis. - Bonn, 2021. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-64662
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-64662,
author = {{Xiaolong Wu}},
title = {Promotion of antitumor activity of CIK cells by targeting the NKG2D axis},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2021,
month = nov,

note = {CIK cells are an ex vivo expanded heterogeneous cell population with an enriched NK-T phenotype (CD3+CD56+). Due to the convenient and inexpensive expansion capability, together with low incidence of GVHD in allogeneic cancer patients, CIK cells are a promising candidate for immunotherapy. It is well known that NKG2D plays an important role in CIK cell-mediated antitumor activity, thus upregulation of NKG2D ligands on tumor cells might elevate the immune response of CIK to these tumor targets. However, it still remains unclear whether NKG2D engagement alone is sufficient or if it requires additional co-stimulatory signals (e.g. 2B4) to activate CIK cells. In order to address these issues and assess the in vitro cytotoxicity of CIK cells in a more accurate and efficient way, we first established an improved flow cytometric cytotoxicity assay based on prior studies. Instead of using calibration beads, a fixed acquisition time can be utilized to standardize the flow cyometric assay with similar efficiency but higher stability. Furthermore, the sample acquisition can be shortened to 15 sec for each tube, thereby making this methodology more cost-effective and efficient. Next, we investigated the individual and cumulative contribution of NKG2D and 2B4 to the activation of CIK cells. Unlike resting NK cells, we found NKG2D engagement alone is sufficient to activate CIK cells, inducing deganulation, IFN-γ secretion and LFA-1 activation, while 2B4 alone failed to elicit these activities and only provides synergistic effect on LFA-1 activation with NKG2D. Unexpectedly, NKG2D was unable to costimulate CD3 in the cytotoxicity of CIK cells. These data indicate the divergences in the role of NKG2D between CIK cells and NK (or T) cells. Nevertheless, we demonstrate that NKG2D alone suffices to activate CIK cells, thus strenghthening the idea of targeting the NKG2D axis may promote the antitumor efficacy of CIK cells. To this end, we further investigated whether the upregulaton of NKG2D ligands on tumor targets can incease the sensitivity of CIK cells. By using an anti-MICA α3 domain monoclonal antibody (7C6 mAb), which was shown to specifically inhibit the MICA shedding and stabilize its surface density on tumor cells (Hela and MDA-MB-231), we found that the CIK cell-mediated antitumor activities (including cytotoxicity, degranulation, IFN-γ secretion) were substantially enhanced. The effect was mostly modulated through NKG2D axis as NKG2D blocking offset the 7C6-driven enhancement in these activities. Collectively, the findings presented in this thesis demonstrate that targeting the NKG2D axis is a promissing approach to improve the antimumor activity of CIK cells, suggesting that the combinatory treatment of CIK cells with other therapeutic modalities which are able to induce or upregulate NKG2D ligands holds great potential to improve the clincial response of cancer patients.},
url = {https://hdl.handle.net/20.500.11811/9418}

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