Sialylation of 3-methylcholanthrene-induced fibrosarcoma determines antitumor immune responses during immunoediting.
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.
Cohen
Merav
M
Department of Biotechnology Engineering, Faculty of Engineering, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Elkabets
Moshe
M
Perlmutter
Michal
M
Porgador
Angel
A
Voronov
Elena
E
Apte
Ron N
RN
Lichtenstein
Rachel G
RG
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005260:Female; D005354:Fibrosarcoma / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D005434:Flow Cytometry; D007694:Killer Cells, Natural / Q000276:immunology; D008748:Methylcholanthrene / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D019158:N-Acetylneuraminic Acid / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology
D002273:Carcinogens; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D008748:Methylcholanthrene; D019158:N-Acetylneuraminic Acid