Sialylation of 3-Methylcholanthrene-Induced Fibrosarcoma Determines Antitumor Immune Responses during Immunoediting
Sialylation of 3-Methylcholanthrene-Induced Fibrosarcoma Determines Antitumor Immune Responses during Immunoediting
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DOI：
10.4049/jimmunol.1001635
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发表时间：
2010-11-15
影响因子：
4.4
通讯作者：
Lichtenstein, Rachel G.
中科院分区：
文献类型：
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作者：
Cohen, Merav;Elkabets, Moshe;Lichtenstein, Rachel G.
肿瘤细胞的唾液酸化涉及其恶性肿瘤的各个方面（增殖、运动、侵袭和转移）;然而，尚未研究其对影响肿瘤细胞免疫原性的免疫编辑过程的影响。我们已经表明，在免疫编辑受损的小鼠中，例如在IL-1 α（-/-）和IFN γ（-/-）小鼠中，3-甲基胆蒽诱导的纤维肉瘤细胞具有免疫原性，并伴随着低水平的表面唾液酸化，而来自野生型小鼠的肿瘤细胞是非免疫原性的，并具有较高水平的表面唾液酸化。为了研究与肿瘤细胞相互作用涉及表面唾液酸残基的免疫机制，我们使用了高度唾液酸化的3-甲基胆蒽诱导的野生型小鼠非免疫原性纤维肉瘤细胞系，这些细胞系用唾液酸酶处理以模拟免疫原性肿瘤细胞变体。体内和体外实验表明，肿瘤细胞的去唾液酸化降低了它们的生长并诱导NK细胞的细胞毒性。此外，唾液酸酶处理的肿瘤细胞更好地激活NK细胞分泌IFN-γ。NK细胞上的NKG 2D激活受体被证明参与与肿瘤细胞上的去唾液酸化配体的相互作用，其性质仍不清楚。因此，在免疫编辑过程中选择的肿瘤细胞上的唾液酸化程度可能已经演变为具有低内在免疫原性的肿瘤细胞或选择可以逃避免疫系统或破坏其功能的肿瘤细胞的重要机制。当免疫编辑受损时，例如在IFN-γ（-/-）和IL-1 α（-/-）小鼠中，明显的肿瘤由去唾液酸化的肿瘤细胞组成，这些肿瘤细胞与免疫监视细胞更好地相互作用。免疫学杂志，2010，185：5869-5878。
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-1 alpha(-/-) and IFN gamma(-/-) 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-gamma 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-gamma(-/-) and IL-1 alpha(-/-) mice, the overt tumor consists of desialylayed tumor cells that interact better with immunosurveillance cells. The Journal of Immunology, 2010, 185: 5869-5878.