Expression of immune checkpoint molecules in endometrial carcinoma

Abstract

Abstract. The main obstacle in the development of an effective tumor vaccine is the inherent ability of tumors to evade immune responses. Tumors often use common immune mechanisms and regulators to evade the immune system. The present study aimed to analyze the expression levels of indoleamine 2,3-dioxygenase (IDO), programmed death-ligand (PD-L) 1, PD-L2, B7-H4, galectin-1 and galectin-3 in tissue samples from patients with endometrial carcinoma, in order to detect the immunosuppressive environment of endometrial carcinomas. The levels of IDO, PD-L1, PD-L2 and B7-H4 were analyzed by immunohistochemical methods, and the levels of galectin-1 and galectin-3 in tumor lysates were determined using ELISA. PD-L2 was expressed at low levels in the majority of tumor samples. IDO expression was detected in 38, 63 and 43% of primary endometrial carcinoma, recurrent endometrial carcinoma, and metastatic endometrial carcinoma specimens, respectively. Positive expression rates for PD-L1 were 83% in primary endometrial carcinoma, 68% in recurrent endometrial carcinoma, and 100% in metastatic endometrial carcinoma, whereas B7-H4 expression was detected in 100% of both primary endometrial carcinoma and recurrent endometrial carcinoma samples, and in 96% of metastatic endometrial carcinoma specimens. The expression levels of galectin-1 and galectin-3 were not significantly different between the normal and tumor specimens. The results of the present study suggest that the interaction between PD-1/PD-L1 and B7-H4 may be a potential target for immune intervention in the treatment of endometrial carcinoma. Furthermore, the results may provide the basis for immunosuppressant therapy in the treatment of patients with uterine cancer.

Indoleamine 2,3-dioxygenase in endometrial cancer: a targetable mechanism of immune resistance in mismatch repair-deficient and intact endometrial carcinomas

“…Tumoral expression of PD-L1 is just one of many potential mechanisms of immune evasion, and there are little data on how the concomitant presence of other anti-immune defenses could interfere with effectiveness of anti-PD-1/ PD-L1 therapies in solid cancers, including endometrial carcinomas. Tumor expression of the immune modulatory enzyme IDO could, for instance, reduce the effectiveness of these therapies by rendering tumor-associated cytotoxic T cells dysfunctional, as exposing a tumor to immune recognition is of little utility if the immune system cannot effectively eliminate it [14,15].…”

“…Furthermore, IDO has been shown to have relevance in endometrial cancers where its expression correlates with impaired T-cell infiltration and worsened survival [16][17][18]. Work from Liu et al [14] revealed IDO expression of at least 1% in 57% of endometrial carcinomas, with significantly higher rates (63% vs. 38%, p < 0.01) in recurrent vs. primary cancers. Ino et al identified IDO expression in 49% of endometrial cancers using a cutoff of 5% tumoral expression, and found IDO was positively correlated with myometrial invasion, nodal metastasis, lymphovascular space involvement, and elevated CD3 + and CD8 + tumor-infiltrating and peritumoral lymphocytes [16,17].…”

“…However, co-opting the PD-L1 pathway is only one of many defense mechanisms that tumors can mount to evade host immunity, and interference with this checkpoint may not be independently curative in cancers with multiple modalities of immune resistance [11][12][13]. Another immune modulatory molecule that has been demonstrated in endometrial carcinomas is indoleamine 2,3-dioxygenase (IDO) [14].…”

Integrated analysis reveals candidate mRNA and their potential roles in uterine leiomyomas

“…In the top‐10 downregulated genes, ALDH1A1 was involved in the development of uterine fibroids in an animal model indirectly . LGALS3 was related to endometrial carcinoma . TLR3 was a critical immunomodulator that played an important role in the development of gynecologic cancers .…”

“…32 LGALS3 was related to endometrial carcinoma. 33 TLR3 was a critical immunomodulator that played an important role in the development of Figure 1 Hierarchically clustered heatmap of the top 50 genes that were altered in uterine leiomyomas (UL). gynecologic cancers.…”