1.中山大学附属第一医院器官移植科//广东省器官捐献与移植免疫重点实验室//广东省器官移植国际科技合作基地, 广东 广州 510080
2.中山大学肿瘤防治中心检验科,广东 广州 510060
刘丹平,硕士生,E-mail:liudanp@mail2.sysu.edu.cn
收稿:2021-03-29,
纸质出版:2021-07-20
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刘丹平,池沛冬,梅美华等.EZH1/2抑制剂UNC1999对外周血免疫细胞表型的影响[J].中山大学学报(医学科学版),2021,42(04):494-503.
LIU Dan-ping,CHI Pei-dong,MEI Mei-hua,et al.Effects of EZH1/2 Inhibitor UNC1999 on Immunophenotypes of Peripheral Immune Cells[J].Journal of Sun Yat-sen University(Medical Sciences),2021,42(04):494-503.
刘丹平,池沛冬,梅美华等.EZH1/2抑制剂UNC1999对外周血免疫细胞表型的影响[J].中山大学学报(医学科学版),2021,42(04):494-503. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2021.0403.
LIU Dan-ping,CHI Pei-dong,MEI Mei-hua,et al.Effects of EZH1/2 Inhibitor UNC1999 on Immunophenotypes of Peripheral Immune Cells[J].Journal of Sun Yat-sen University(Medical Sciences),2021,42(04):494-503. DOI: 10.13471/j.cnki.j.sun.yat-sen.univ(med.sci).2021.0403.
目的
2
探讨EZH1/2抑制剂UNC1999对外周血免疫细胞表型的影响。
方法
2
用CCK-8法检测UNC1999作用于外周血单个核细胞(PBMC)后的细胞存活率;多色流式细胞术分析免疫细胞表型。
结果
2
相比对照组,UNC1999组经典型单核细胞(CD14
++
CD16
-
)比例上调[(19.53±1.79)%
vs
. (66.60±5.02)%,
t
=13.31,
P
=0.006],中间型单核细胞(CD14
++
CD16
+
)和非经典型单核细胞(CD14
+
CD16
+
)比例下调[(35.08±3.97)%
vs
. (15.42±2.89)%,
t
=6.130,
P
=0.026;(35.50±3.53)%
vs
. (8.40±3.12)%,
t
=25.740,
P
=0.002]; CD56
dim
CD16
+
、CD56
dom
CD16
+
NK细胞亚群比例下调[(3.39±0.86)%
vs
. (0.27±0.06)% ,
t
=4.882,
P
=0.040;(80.50±0.64)%
vs
. (0.63±0.23)% ,
t
=133.100,
P
<
0.000 1];初始B细胞比例上调[(10.67±1.76)%
vs
. (37.99±3.76)%,
t
=17.690,
P
=0.003],记忆B细胞、过渡B细胞、浆细胞比例下调[(23.39±4.20)%
vs
. (11.82±1.90)%,
t
=7.059,
P
=0.020;(3.58±0.47)%
vs
. (1.52±0.56)%,
t
=26.970,
P
=0.001;(0.18±0.03)%
vs
. (0.00±0.00)%,
t
=8.647,
P
=0.013];DC比例上调[(0.20±0.05)%
vs
. ( 1.38±0.13)%,
t
=16.500,
P
=0.004],其中pDC/DC下调[(24.90±1.95)%
vs
. (12.70±2.11)%,
t
=7.566,
P
=0.017],mDC/DC上调[(32.41±13.14)%
vs
. (60.87±8.43)%,
t
=8.252,
P
=0.014];CD8
+
T细胞亚群中CD8
+
中枢记忆T细胞、CD8
+
PD-1
+
比例上调[(5.62±1.24)%
vs
. (18.38±2.34)%,
t
=15.600,
P
=0.004 ;(2.50±1.02)%
vs
. (18.34±2.69)% ,
t
=8.822,
P
=0.013],CD8
+
效应记忆T细胞比例下调[(28.27±10.15)%
vs
. (15.62±9.48)% ,
t
=19.480,
P
=0.003];CD4
+
T细胞亚群中CD4
+
CD27
+
比例下调[(82.77±2.66)%
vs
. (56.00±9.01)%,
t
=5.715,
P
=0.029]。其余细胞亚群差异无统计学意义(
P
>
0.05)。
结论
2
UNC1999可以改变PBMC免疫细胞表型。
Objective
2
To investigate the effects of EZH1/2 inhibitor UNC1999 on the immune cell phenotypes in peripheral blood of healthy adults.
Methods
2
CCK8 assay was used to measure the cell viability of peripheral blood mononuclear cells (PBMC). Multicolor flow cytometry was performed to analyze the immunophenotypes.
Results
2
Compared with DMSO group, UNC1999 group showed increased classical monocytes (CD14
++
CD16
-
) [(19.53±1.79)%
vs
. (66.60±5.02)%,
t
=13.31,
P
=0.006), decreased intermediate monocytes (CD14
++
CD16
+
) and non-classical monocytes (CD14
+
CD16
+
) [(35.08±3.97)%
vs
. (15.42±2.89)%,
t
=6.130,
P
=0.026; (35.50±3.53)%
vs
. (8.40±3.12)%,
t
=25.740,
P
=0.002]. The proportions of CD56
dim
CD16
+
, CD56
dom
CD16
+
in UNC1999 group were lower [(3.39±0.86)%
vs
. (0.27±0.06)%,
t
=4.882,
P
=0.040; (80.50±0.64)%
vs
. (0.63±0.23)%,
t
=133.100,
P
<
0.000 1]. UNC1999 group exhibited higher frequency of naive B cells [(10.67±1.76)%
vs
. (37.99±3.76)%,
t
=17.690,
P
=0.003], lower frequency of memory B cells, transitional B cells, plasmablasts B cells [(23.39±4.20)%
vs
. (11.82±1.90)%,
t
=7.059,
P
=0.020; (3.58±0.47)%
vs
. (1.52±0.56)%,
t
=26.970,
P
=0.001; (0.18±0.03)%
vs
. (0.00±0.00)%,
t
=8.647,
P
=0.013]. The percentage of DC and mDC/DC was significantly elevated in UNC1999 group [(0.20±0.05)%vs.(1.38±0.13)%,
t
=16.500,
P
=0.004; (32.41±13.14)%
vs
. (60.87±8.43)%,
t
=8.252,
P
=0.014], with a significantly decreased percentage of pDC/DC [(24.90±1.95)%
vs
. (12.70±2.11)%,
t
=7.566,
P
=0.017]. Higher proportions of CD8
+
central memory T cells (TCM) and CD8
+
PD-1
+
[(5.62±1.24)%
vs
. (18.38±2.34)%,
t
=15.600,
P
=0.004; (2.50±1.02)%
vs
. (18.34±2.69)%,
t
=8.822,
P
=0.013], but lower proportions of CD8
+
effective memory T cells (TEM) and CD4
+
CD27
+
were observed in UNC1999 [(28.27±10.15)%
vs
. (15.62±9.48)%,
t
=19.480,
P
=0.003; (82.77±2.66)%
vs
. (56.00±9.01)%,
t
=5.715,
P
=0.029]. No statistical difference was found in other cell subsets (
P
>
0.05).
Conclusion
2
UNC1999 can lead to changes in PBMC immunophenotypes.
Chen J , Liang X , Zhang S , et al . Two faces of bivalent domain regulate VEGFA responsiveness and angiogenesis [J]. Cell Death Dis , 2020 , 11 ( 1 ): 75 .
Mousavi K , Zare H , Wang AH , et al . Polycomb protein Ezh1 promotes RNA polymerase II elongation [J]. Mol Cell , 2012 , 45 ( 2 ): 255 - 262 .
Fioravanti R , Stazi G , Zwergel C , et al . Six years (2012-2018) of researches on catalytic EZH2 inhibitors: The boom of the 2-pyridone compounds [J]. Chem Rec , 2018 , 18 ( 12 ): 1818 - 1832 .
Konze KD , Ma A , Li F , et al . An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1 [J]. ACS Chem Biol , 2013 , 8 ( 6 ): 1324 - 1334 .
Li W , Bi C , Han Y , et al . Targeting EZH1/2 induces cell cycle arrest and inhibits cell proliferation through reactivation of p57(CDKN1C) and TP53INP1 in mantle cell lymphoma [J]. Cancer Biol Med , 2019 , 16 ( 3 ): 530 - 541 .
Rizk M , Rizq O , Oshima M , et al . Akt inhibition synergizes with polycomb repressive complex 2 inhibition in the treatment of multiple myeloma [J]. Cancer Sci , 2019 , 110 ( 12 ): 3695 - 3707 .
Rezaei S , Hosseinpourfeizi MA , Moaddab Y , et al . Contribution of DNA methylation and EZH2 in SRBC down-regulation in gastric cancer [J]. Mol Biol Rep , 2020 , 47 ( 8 ): 5721 - 5727 .
Arbuckle JH , Gardina PJ , Gordon DN , et al . Inhibitors of the histone methyltransferases EZH2/1 induce a potent antiviral state and suppress infection by diverse viral pathogens [J]. mBio , 2017 , 8 ( 4 ): e01141-17 .
Ben Mkaddem S , Aloulou M , Benhamou M , et al . Role of FcgammaRIIIA (CD16) in IVIg-mediated anti-inflammatory function [J]. J Clin Immunol , 2014 , 34 ( S1 ): S46 - 50 .
Aloulou M , Ben Mkaddem S , Biarnes-Pelicot M , et al . IgG1 and IVIg induce inhibitory ITAM signaling through FcgammaRIII controlling inflammatory responses [J]. Blood , 2012 , 119 ( 13 ): 3084 - 3096 .
Wolf AA , Yanez A , Barman PK , et al . The ontogeny of monocyte subsets [J]. Front Immunol , 2019 , 10 : 1642 .
Wong KL , Yeap WH , Tai JJ , et al . The three human monocyte subsets: implications for health and disease [J]. Immunol Res , 2012 , 53 ( 1-3 ): 41 - 57 .
Vasse M , Zuber B , Goubeau L , et al . A low level of CD16(pos) monocytes in SARS-CoV-2 infected patients is a marker of severity [J]. Clin Chem Lab Med , 2021 . doi: 10.1515/cclm-2020-1801 http://dx.doi.org/10.1515/cclm-2020-1801 .
Zwirner NW , Domaica CI , Fuertes MB . Regulatory functions of NK cells during infections and cancer [J]. J Leukoc Biol , 2021 , 109 ( 1 ): 185 - 194 .
Kaur K , Safaie T , Ko MW , et al . ADCC against MICA/B is mediated against differentiated oral and pancreatic and not stem-like/poorly differentiated tumors by the NK cells; loss in cancer patients due to down-modulation of CD16 receptor [J]. Cancers (Basel) , 2021 , 13 ( 2 ): 239 .
Chan A , Hong DL , Atzberger A , et al . CD56bright human NK cells differentiate into CD56dim cells: role of contact with peripheral fibroblasts [J]. J Immunol , 2007 , 179 ( 1 ): 89 - 94 .
Ferlazzo G , Thomas D , Lin SL , et al . The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic [J]. J Immunol , 2004 , 172 ( 3 ): 1455 - 1462 .
Damele L , Amaro A , Serio A , et al . EZH1/2 Inhibitors favor ILC3 development from human HSPC-CD34(+) cells [J]. Cancers (Basel) , 2021 , 13 ( 2 ): 319 .
Caganova M , Carrisi C , Varano G , et al . Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis [J]. J Clin Invest , 2013 , 123 ( 12 ): 5009 - 5022 .
Su IH , Basavaraj A , Krutchinsky AN , et al . Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement [J]. Nat Immunol , 2003 , 4 ( 2 ): 124 - 131 .
Abdalkader L , Oka T , Takata K , et al . Aberrant differential expression of EZH1 and EZH2 in Polycomb repressive complex 2 among B- and T/NK-cell neoplasms [J]. Pathology , 2016 , 48 ( 5 ): 467 - 482 .
Collin M , Bigley V . Human dendritic cell subsets: an update [J]. Immunology , 2018 , 154 ( 1 ): 3 - 20 .
Wonderlich ER , Barratt-Boyes SM . A dendrite in every pie: myeloid dendritic cells in HIV and SIV infection [J]. Virulence , 2012 , 3 ( 7 ): 647 - 653 .
Marcel N , Hedrick SM . A key control point in the T cell response to chronic infection and neoplasia: FOXO1 [J]. Curr Opin Immunol , 2020 , 63 : 51 - 60 .
Shinohara T , Taniwaki M , Ishida Y , et al . Structure and chromosomal localization of the human PD-1 gene (PDCD1) [J]. Genomics , 1994 , 23 ( 3 ): 704 - 706 .
Ishida Y , Agata Y , Shibahara K , et al . Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death [J]. EMBO J , 1992 , 11 ( 11 ): 3887 - 3895 .
Sharpe AH , Pauken KE . The diverse functions of the PD1 inhibitory pathway [J]. Nat Rev Immunol , 2018 , 18 ( 3 ): 153 - 167 .
Buchan SL , Rogel A , Al-Shamkhani A . The immunobiology of CD27 and OX40 and their potential as targets for cancer immunotherapy [J]. Blood , 2018 , 131 ( 1 ): 39 - 48 .
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