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.

We evaluated the patterns of sialylation on fibrosarcoma cell lines arising following 3-methylcholanthrene treatments of wild-type and IL-1alpha-deficient mice; the former induced progressive tumors, whereas the latter cell lines induced regressing tumors or failed to develop into tumors in mice due to immune rejection. In regressing tumors, terminating alpha2-6-Neu5Ac residues were present at lower levels than in progressively growing tumors. In both tumor cells, the amount of alpha2-6-Neu5Ac residues was higher by an order of magnitude relative to the amount expressed in primary fibroblasts harvested from IL-1alpha-deficient and wild-type mice. We focused on membrane proteins, which may interact with the immune system. Interestingly, HSP65, grp75, and gp96 were found on the surfaces of malignant cells and were shown to possess sialylated N-glycans. The amount of trisialylated glycans on gp96 and HSP65 and monosialylated glycans on grp75 of regressing cells was significantly lower than in progressively growing cells, suggesting a dependency of these specific glycoforms on anti-tumor immunity.