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. 2021 Apr;70(4):981-988.
doi: 10.1007/s00262-020-02763-w. Epub 2020 Oct 21.

Notch signaling defects in NK cells in patients with cancer

Gulnur K Zakiryanova  1 , Elena Kustova  2 , Nataliya T Urazalieva  2 , Emile T Baimukhametov  3 , Valeriy A Makarov  4 , Gulmariya M Turaly  5 , Galina V Shurin  6 , Zarema M Biyasheva  7 , Narymzhan N Nakisbekov  5 , Michael R Shurin  8
Affiliations

Notch signaling defects in NK cells in patients with cancer

Gulnur K Zakiryanova et al. Cancer Immunol Immunother. 2021 Apr.

Abstract

Altered expressions of proto-oncogenes have been reported during normal lymphocytes mitogenesis and in T and B lymphocytes in patients with autoimmune diseases. We have recently demonstrated a significantly decreased expression of c-kit and c-Myc in NK cells isolated from patients with cancer, which might be related to the functional deficiency of NK cells in the tumor environment. Here, focusing on the regulatory mechanisms of this new clinical phenomenon, we determined expression of c-Myc, Notch1, Notch2, p-53, Cdk6, Rb and phosphorylated Rb in NK cells isolated from the healthy donors and cancer patients. The results of our study revealed a significant down-regulation of expression of Notch receptors and up-regulation of Cdk6 expression in NK cells in cancer, while no significant changes in the expression of p53 and Rb proteins were seen. These data revealed novel signaling pathways altered in NK cells in the tumor environment and support further investigation of the origin of deregulated expression of proto-oncogenes in NK cells patients with different types of cancer.

Keywords: NK cells; Notch1; Notch2; T cells; c-myc.

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Conflict of interest statement

The authors declare no potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Differences in Notch1 expression in NK cells harvested from healthy donors and cancer patients. NK cells were isolated from the peripheral blood samples by negative selection using Dynabeads. The relative Notch1 expression was determined by flow cytometry on stained NK cells from healthy donors, patients with lung and gastric cancer. a The results of flow cytometry data from a representative experiment are shown. b Data of mean fluorescent intensity (MFI) are shown as the mean ± SEM (N = 11–20). *p < 0.05; **p < 0.01; one-way ANOVA
Fig. 2
Fig. 2
Differences in Notch2 expression in NK cells harvested from healthy donors and cancer patients. NK cells were isolated from the peripheral blood samples by negative selection using Dynabeads. Notch2 expression was determined by flow cytometry on stained isolated peripheral NK cells from healthy donors, patients with lung and gastric cancer. a The results of flow cytometry data from a representative experiment are shown. b Data of mean fluorescent intensity (MFI) are shown as the mean ± SEM (one-way ANOVA, N = 15–29). **p < 0.01
Fig. 3
Fig. 3
Differences in the levels of Cdk6 expression in NK cells harvested from healthy donors and cancer patients. NK cells were isolated from the peripheral blood samples by negative selection using Dynabeads. Cdk6 expression was determined by flow cytometry intracellularly in NK cells from healthy donors, patients with lung and gastric cancer. a The results of flow cytometry data from a representative experiment are shown. b Data of mean fluorescent intensity (MFI) are shown as the mean ± SEM (one-way ANOVA, N = 17–32). *p < 0.05
Fig. 4
Fig. 4
Differences in c-myc mRNA expression in T cells harvested from healthy donors and cancer patients. T cells were isolated from the peripheral blood samples by positive selection using BD IMag™ anti-human CD3 Particles DM, incubated in complete medium for 20 h. C-myc-mRNA expression in peripheral T cells from healthy donors and patients with lung and cancer was determined by Smart Flare. a Actual experimental results are shown. b Data of mean fluorescent intensity (MFI) are shown as the mean ± SEM (one-way ANOVA, N = 9). ***p = 0.001
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