Abstract 6138: High Globo-H expression associated with poor survival of gastric cancer patients and enriched PD-L1 expression

Abstract

Abstract Background: Globo series antigens have been implicated in playing important roles in enhancing tumor growth through protecting tumor cells from apoptosis, suppressing T cell activity in the tumor microenvironment and promoting endothelial cell angiogenesis. Globo-H (GH), a globo-series glycosphingolipid (GSL) antigen that is synthesized by key enzymes β1,3-galactosyltransferase V (β3GalT5), fucosyltransferase (FUT) 1 and 2, is highly expressed on a variety of epithelial cancers rendering it a promising target for cancer immunotherapy. GH is reported to associate the EGFR mutant and PD-L1 expression in non-small cell lung cancer (NSCLC) patients. In addition, GH-targeting antibody-drug conjugate (ADC) OBI-999 has been demonstrated an excellent tumor growth inhibition potency in animal models across multiple cancer types including gastric cancer (GC). This study aims to further investigate the GH roles in GC. Methods: Prognostic roles of β3GalT5, FUT1 and FUT2 in GC patients were accessed through the “Kaplan-Meier plotter” database. The level of GH expression was evaluated in clinical adenocarcinoma samples from 105 patients with GC by immunohistochemistry (IHC) using H-score. Microwestern protein array analysis was performed in sorted GC NCI-N87 cells. FACS methods were also employed to measure the levels of PD-L1 and phospho-EGFRs in multiple cancer cell lines. Results: Significant correlations were observed between high mRNA expression of synthesized key enzymes and worse overall survival (OS)/post-progression survival for all 498 GC patients. Positive GH expression (H score≥20; 33.3%) was significantly associated with a poor disease specific survival in all samples (at 15 years; p=0.029), a poor OS in poorly differentiated tumors (p=0.033), and invasiveness (p=0.013), indicating GH expression was a potential prognostic factor in GC. Sorted NCI-N87 cells with high level of endogenous GH expression showed a relatively greater proliferative activity compared with cells expressing low level of GH. Microwestern array analysis on sorted cells indicated upregulations of phospho-AKT/P38/JNK, Cyclin D1 and Cyclin E1 protein in high GH expression NCI-N87 cells, which implicated a mechanistic link between high GH and tumor promoting signals in GC. In addition, GH level was shown to be correlated with cell surface expression level of PD-L1 in NCI-N87, SNU-16, HCC-1428, ACHN, and TKI-resistant H1975 NSCLC cancer cells. Higher phospho-EGFRs (Tyr1068 and Tyr1173) were detected in high GH level of H1975 cells, which is consistent with the results from previous studies showing association between GH level and EGFR mutant/PD-L1 expression in NSCLC. Conclusions: GH level was associated with the survival of GC patients and positively correlated with cell surface PD-L1 expression in vitro. Therefore, GH-targeting therapy has a potential application for the treatment of GC patients. Citation Format: Tzer-Min Kuo, Hui-Ting Hsu, Cheng-Yen Wei, Ming-Tain Lai, Chun-Te Chen. High Globo-H expression associated with poor survival of gastric cancer patients and enriched PD-L1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6138.