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Suppression of CD56bright NK cells in breast cancer patients is associated with the PD-1 and TGF-βRII expression

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Abstract

Background

Natural killer (NK) cells, as professional cytotoxic cells, play a key role against cancer in the early and metastatic stages. Their functional defects are highly associated with the initiation or progression of breast cancer (BC). Here, we investigated the phenotypic characterization of NK cells in 26 newly diagnosed BC patients in comparison to 12 healthy counterparts.

Methods

Expression of CXCR3 and PD-1, and also NKG2D, and TGF-βRII were studied on CD56dim and CD56bright NK cells from fresh peripheral blood (PB) samples using flow cytometry. The plasma levels of IFN-γ and soluble MIC-A levels were also assessed by ELISA.

Results

Both CD56dim and CD56bright NK subtypes showed lower CXCR3 and NKG2D expression in BC patients than healthy subjects. Furthermore, patients’ CD56bright NK cells significantly showed higher expression levels of TGF-βRII and PD-1. Interestingly, increased concentration of MIC-A level in plasma of BC patients was associated with the higher TGF-βRII and PD-1 expression in all NK cells, while the plasma level of IFN-γ was associated with the lower TGF-βRII expression on CD56bright NK cells in these patients.

Conclusion

Our results demonstrated phenotypically suppressed-NK cells, especially in the CD56bright subset of BC patients. It specifies their potential incompetence and outlines decrement of their anti-tumor activity, which could be interrelated with the tumor pathogenesis, TME immunosuppression, and so disease progression. The induction of compensatory mechanisms revives NK cells function and could be used in combination with the conventional treatments as a putative therapeutic approach for targeted immunotherapy.

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Abbreviations

PB:

Peripheral blood

NK cell:

Natural killer cell

BC:

Breast cancer

NKG2D:

Natural killer group 2D

CXCR3:

C-X-C motif chemokine receptor 3

PD-1:

Programmed death receptor-1

TGF-βRII:

Transforming growth factor beta receptor II

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Funding

This article was granted by Iran National Science Foundation (INSF) 0.13039/501100003968, with Grant No. 96010101 and Golestan University of Medical Sciences with Grant No. 110632.

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Authors and Affiliations

  1. Student Research Committee, Golestan University of Medical Sciences, Gorgan, Iran

    Elaheh Arianfar

  2. Department of Immunology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

    Elaheh Arianfar & Ali Memarian

  3. Cancer Research Center, Golestan University of Medical Sciences, Gorgan, Iran

    Seyed Reza Khandoozi

  4. Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran

    Saeed Mohammadi

  5. Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran

    Ali Memarian

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  1. Elaheh Arianfar
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  4. Ali Memarian
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Correspondence to Ali Memarian.

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This study was approved by the ethics committee of Golestan University of Medical Sciences (No: IR.GOUMS.REC.1398.020).

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Supplementary file1. Phenotypic analysis of TGF-βRII, NKG2D, PD-1, and CXCR3 on peripheral blood. CD56dim NK cells (A) and CD56bright NK cells (B) in BC patients. Flow cytometry data are presented as mean fluorescence intensity (MFI) of TGF-βRII+, NKG2D+, PD-1+, and CXCR3+ NK cells in 26 BC patients and 12 healthy donors. Analysis was performed using the independent sample T-test. p-values lower than 0.05 were considered statistically significant. Data of each bar demonstrates means ±SE. NS= not significant. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 (TIF 4839 KB)

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Arianfar, E., Khandoozi, S.R., Mohammadi, S. et al. Suppression of CD56bright NK cells in breast cancer patients is associated with the PD-1 and TGF-βRII expression. Clin Transl Oncol 25, 841–851 (2023). https://doi.org/10.1007/s12094-022-02997-3

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