Mifepristone inhibited the expression of B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis

Abstract

Background: The immune mechanism was shown to be involved in the development of adenomyosis. The aim of the current study was to evaluate the expression of the immune checkpoints B7-H2, B7-H3, B7-H4 and PD-L2 in adenomyosis and to explore the effect of mifepristone on the expression of these immune checkpoints.

Methods: The expression of B7-H2, B7-H3, B7-H4 and PD-L2 in normal endometria and adenomyosis patient samples treated with or without mifepristone was determined by immunohistochemistry analysis.

Results: In adenomyosis patient samples, the expression of B7-H2, B7-H3 and B7-H4 was increased in the eutopic and ectopic endometria compared with normal endometria, both in the proliferative and secretory phases. Moreover, the expression of B7-H2 and B7-H3 was higher in adenomyotic lesions than in the corresponding eutopic endometria, both in the proliferative and secretory phases. The expression of PD-L2 was higher in adenomyotic lesions than in normal endometria in both the proliferative and secretory phases. In the secretory phase but not the proliferative phase, the expression of B7-H4 and PD-L2 in adenomyotic lesions was significantly higher than that in the corresponding eutopic endometria. In normal endometria and eutopic endometria, the expression of B7-H4 was elevated in the proliferative phase compared with that in the secretory phase, while in the ectopic endometria, B7-H4 expression was decreased in the proliferative phase compared with the secretory phase. In addition, the expression of B7-H2, B7-H3, B7-H4 and PD-L2 was significantly decreased in adenomyosis tissues after treatment with mifepristone.

Conclusions: The expression of the immune checkpoint proteins B7-H2, B7-H3, B7-H4 and PD-L2 is upregulated in adenomyosis tissues and is downregulated with mifepristone treatment. The data suggest that B7 immunomodulatory molecules are involved in the pathophysiology of adenomyosis.

Keywords: Adenomyosis; B7-H2; B7-H3; B7-H4; Mifepristone; PD-L2.

Fig. 1

Immunoexpression and comparison of B7-H2 in normal, eutopic and ectopic endometrium of adenomyosis treated with and without mifepristone. a Ectopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); b Ectopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); c Eutopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); d Eutopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); e Normal endometrium of proliferative phase in patients without adenomyosis (n = 47); f Normal endometrium of secretory phase in patients without adenomyosis (n = 27); g Ectopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); h and i Eutopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); j Immunoscore comparation of B7-H2 between each groups,* P < 0.05, ** P < 0.01. a- i magnification: × 100

Fig. 2

Immunoexpression and comparison of B7-H3 in normal, eutopic and ectopic endometrium of adenomyosis treated with and without mifepristone. a Ectopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); b Ectopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); c Eutopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); d Eutopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); e Normal endometrium of proliferative phase in patients without adenomyosis (n = 47); f Normal endometrium of secretory phase in patients without adenomyosis (n = 27); g Ectopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); h and i eutopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); j Immunoscore comparation of B7-H3 between each groups, * P < 0.05, ** P < 0.01. a- i magnification: × 100;

Fig. 3

Immunoexpression and comparison of B7-H4 in normal, eutopic and ectopic endometrium of adenomyosis treated with and without mifepristone. a Ectopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); b Ectopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); c Eutopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); d Eutopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); e Normal endometrium of proliferative phase in patients without adenomyosis (n = 47); f Normal endometrium of secretory phase in patients without adenomyosis (n = 27); g Ectopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); h and i Eutopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); j Immunoscore comparation of B7-H4 between each groups,* P < 0.05, ** P < 0.01. a- i magnification: × 100

Fig. 4

Immunoexpression and comparison of PD-L2 in normal, eutopic and ectopic endometrium of adenomyosis treated with and without mifepristone. a Ectopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); b Ectopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); c Eutopic endometrium of proliferative phase in patient with untreated adenomyosis (n = 35); d Eutopic endometrium of secretory phase in patient with untreated adenomyosis (n = 23); e Normal endometrium of proliferative phase in patients without adenomyosis (n = 47); f Normal endometrium of secretory phase in patients without adenomyosis (n = 27); g Ectopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); h and i. Eutopic endometrium in patient with mifepristone-treated adenomyosis (n = 11); j Immunoscore comparation of PD-L2 between each groups,* P < 0.05, ** P < 0.01. a- i magnification: × 100;

Fig. 5

Schematic representation of B7-H2, B7-H3, B7-H4 and PD-L2 with their respective receptor