Abstract: Intratumoral heterogeneity is known to drive tumor recurrence and eventual treatment failure. In particular, cancer stem cells (CSCs), a small subset of cells within heterogeneous tumor cells, are capable of adapting to the tumor microenvironment, resisting chemotherapy, and driving metastatic progression. Glycosylation has been implicated in the regulation of cell pluripotency and cancer pathogenesis. However, the role of CSC-associated glycosylation changes in ovarian cancer metastatic progression remains elusive. In this study, we showed that fucosyltransferase 5 (FUT5) is significantly associated with advanced stage (p= 0.0058) and poor overall survival (p= 0.0163) in ovarian cancer patients (HGSOC, n= 53). Multiplex immunofluorescence staining analysis of T cell markers showed that high FUT5 expression in ovarian tumors is negatively linked to an unconventional CD4-CD8- (double negative, DN) T cell subset, IFNγ response, and activation of cytotoxic T cells and NK cells (Ki67+ cells). Unconventional T cells are emerging as important modulators of the anti-tumor immune response within the tumor microenvironment. They possess the unique ability to activate both innate and adaptive immune response through vast production of IFNγ. In an in vivo experiment using a humanized mice model, FUT5 KO in metastatic-CSCs (M-CSCs) suppressed metastatic tumor growth and increased effector cytotoxic T cells. In addition, while the NS control tumors showed no response to anti-PD-1 immune checkpoint blockade (ICB) treatment, activation of unconventional NKT cells sensitized NS tumors to ICB treatment. Together, the study reveals a novel mechanism of immune modulation mediated by M-CSCs in ovarian cancer. Our results on FUT5-dependent attenuation of unconventional DN T cells could offer valuable insights for the development of novel therapeutic strategies aimed at enhancing the prognosis of ovarian cancer patients.
Funding Source: This research is supported by RGC SRFS2223-7S05, HMRF 08192286 and LSCCB under the Health@InnoHK Program launched by ITC, HKSAR.
