Sialylation of 3-Methylcholanthrene–Induced Fibrosarcoma Determines Antitumor Immune Responses during Immunoediting

Abstract

Sialylation of tumor cells is involved in various aspects of their malignancy (proliferation, motility, invasion, and metastasis); however, its effect on the process of immunoediting that affects tumor cell immunogenicity has not been studied. We have shown that in mice with impaired immunoediting, such as in IL-1α−/− and IFNγ−/− mice, 3-methylcholanthrene–induced fibrosarcoma cells are immunogenic and concomitantly bear low levels of surface sialylation, whereas tumor cells derived from wild type mice are nonimmunogenic and bear higher levels of surface sialylation. To study immune mechanisms whose interaction with tumor cells involves surface sialic acid residues, we used highly sialylated 3-methylcholanthrene–induced nonimmunogenic fibrosarcoma cell lines from wild type mice, which were treated with sialidase to mimic immunogenic tumor cell variants. In vivo and in vitro experiments revealed that desialylation of tumor cells reduced their growth and induced cytotoxicity by NK cells. Moreover, sialidase-treated tumor cells better activated NK cells for IFN-γ secretion. The NKG2D-activating receptor on NK cells was shown to be involved in interactions with desialylated ligands on tumor cells, the nature of which is still not known. Thus, the degree of sialylation on tumor cells, which is selected during the process of immunoediting, has possibly evolved as an important mechanism of tumor cells with low intrinsic immunogenicity or select for tumor cells that can evade the immune system or subvert its function. When immunoediting is impaired, such as in IFN-γ−/− and IL-1α−/− mice, the overt tumor consists of desialylayed tumor cells that interact better with immunosurveillance cells.

Glycobiology of cell death: when glycans and lectins govern cell fate

“…56 Interestingly, a2-6 sialylation also showed significant effects on cancer immunoediting, a process in which cell death plays a critical role. 57 An interesting example of how lectin-receptor interactions control inflammatory response has been shown for galectin-8. Binding of galectin-8 to CD44 activates the proapoptotic machinery in joint inflammatory cells and promotes relief of inflammation.…”

Interactions between Siglec-7/9 receptors and ligands influence NK cell–dependent tumor immunosurveillance

“…Distinctly glycosylated tumor antigens on the cell surface or on secreted molecules (e.g., mucins) are diagnostically exploited as tumor markers (e.g., CA125, MUC1, CEA, and CA19-9). Sialoglycans influence many critical steps in tumor biology, including immunoediting, tumor growth and proliferation, invasion, metastasis, and angiogenesis; in some instances, their presence has been correlated with poor patient survival (1,2,(5)(6)(7)(8).…”

The immunomodulating roles of glycoproteins in epithelial ovarian cancer

“…Another line of evidence indicating the importance of sialylation in tumor immunology is a recent study in the methylcholanthrene induced fibrosarcoma model (199,200). It was observed that methylcholanthrene induced fibrosarcomas grown in immunecompetent mice expressed high levels of sialic acid on their cell surface.…”

“…It was observed that methylcholanthrene induced fibrosarcomas grown in immunecompetent mice expressed high levels of sialic acid on their cell surface. However, the same type of tumors grown in IL-1alpha −/− and IFN-γ −/− immunocompromised mice expressed lower levels of sialylation (199). Extensive analysis in this model resulted in the understanding that the immune cells were selectively lysing fibrosarcoma cells that were expressing low levels of sialic acids while those expressing high levels of sialic acid were being selectively excluded from immune cell attack.…”