Abstract 6527: Fucosyltransferase 5 promotes immune evasion in ovarian cancer by suppressing double negative T cells

Abstract Emerging evidence suggests that aberrant glycosylation in cancer impact on various stages in the disease progression including immunomodulation, but the underlying mechanisms remain poorly understood. Our previous data demonstrated that fucosyltransferase 5 (FUT5), a glycosyltransferase responsible for the terminal step in synthesizing Lewis antigens, may contribute to peritoneal metastasis of ovarian cancer. In this study, using clinical samples of high grade serous ovarian cancer (HGSOC), the most common subtype, we found that high expression of FUT5 is associated with a worse outcome. By employing multiplex immunohistochemistry (IHC) to examine T cell subsets, we found a significant decrease in CD3+CD4−CD8− (double negative, DN) T cells in FUT5high (n=10) compared to FUT5low samples (n=10), while there is no difference in the abundance of CD8+ cytotoxic T cells, CD4+ helper T cells or CD4+Foxp3+ regulatory T cells. Tumor-infiltrating DN T cells has been shown to mediate potent anti-tumor response. In addition to their cytotoxic capabilities, DN T cells largely exhibit modulatory functions on other T cell subsets. To further investigate, we performed additional IHC staining and observed a significant increase in proliferating (Ki67+) CD8+ tissue resident memory cells, which are known to be important for cancer immunity. In addition, we observed a decrease in metastases in the FUT5 knockdown group, accompanied by an increase in DN T cells in ascites and omental metastatic tumors in humanised mice, as revealed by flow cytometry, confirming a direct immunomodulatory role of FUT5. Together, these findings reveal a novel role of FUT5 in promoting immune evasion by suppressing anti-tumor DN T cells, which could provide novel insights for immunotherapy in HGSOC, which has a low response rate to immune checkpoint inhibitors (This research is supported by RGC SRFS2223-7S05, HMRF 08192286 and LSCCB under the Health@InnoHK Program launched by ITC, HKSAR). Citation Format: S. W. Fung, Sally K. Y. To, A. A. Hassan, Phillip P. C. Ip, Alice S. T. Wong. Fucosyltransferase 5 promotes immune evasion in ovarian cancer by suppressing double negative T cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6527.