Sialic Acid Blockade Suppresses Tumor Growth by Enhancing T-cell-Mediated Tumor Immunity
Sialic Acid Blockade Suppresses Tumor Growth by Enhancing T-cell-Mediated Tumor Immunity
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DOI：
10.1158/0008-5472.can-17-3376
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发表时间：
2018-07-01
期刊：
影响因子：
11.2
通讯作者：
Adema, Gosse J.
中科院分区：
文献类型：
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作者：
Bull, Christian;Boltje, Thomas J.;Adema, Gosse J.
癌细胞表面的唾液酸糖已成为有效的免疫调节剂，有助于免疫抑制微环境和肿瘤免疫逃避。然而，这些糖调节抗肿瘤免疫的机制以及针对它们的治疗策略是有限的。在这里，我们报告了肿瘤内注射唾液酸模拟物Ac（5）3F（ax）Neu 5Ac在体内阻断肿瘤唾液酸表达，并在多种肿瘤模型中抑制肿瘤生长。唾液酸阻断对肿瘤的免疫细胞组成有重大影响，增加肿瘤浸润的自然杀伤细胞和CD 8（+）T细胞数量，同时减少调节性T细胞和髓样调节细胞数量。唾液酸阻断增强细胞毒性CD 8（+）T细胞介导的肿瘤细胞杀伤，部分是通过促进抗原特异性T细胞-肿瘤细胞聚集。唾液酸阻断还与体内肿瘤特异性CD 8（+）T细胞的过继转移协同作用，并通过增加树突状细胞活化和随后的CD 8（+）T细胞应答来增强CpG免疫辅助治疗。总的来说，这些数据强调了唾液酸在肿瘤免疫逃避中的关键作用，并提供了概念证据，即唾液酸阻断为CD 8（+）T细胞介导的肿瘤免疫创造了免疫许可的肿瘤微环境，无论是作为单一治疗还是与其他基于免疫的干预策略组合。唾液酸糖作为免疫抑制肿瘤微环境的重要调节剂发挥作用，限制了有效的抗肿瘤免疫http://cancerres.aacrjournals.org/content/canres/78/13/3574/F1.large.jpg。(C)2018年AACR。
Sialic acid sugars on the surface of cancer cells have emerged as potent immune modulators that contribute to the immunosuppressive microenvironment and tumor immune evasion. However, the mechanisms by which these sugars modulate antitumor immunity as well as therapeutic strategies directed against them are limited. Here we report that intratumoral injections with a sialic acid mimetic Ac(5)3F(ax)Neu5Ac block tumor sialic acid expression in vivo and suppress tumor growth in multiple tumor models. Sialic acid blockade had a major impact on the immune cell composition of the tumor, enhancing tumor-infiltrating natural killer cell and CD8(+) T-cell numbers while reducing regulatory T-cell and myeloid regulatory cell numbers. Sialic acid blockade enhanced cytotoxic CD8(+) T-cell-mediated killing of tumor cells in part by facilitating antigen-specific T-cell-tumor cell clustering. Sialic acid blockade also synergized with adoptive transfer of tumor-specific CD8(+) T cells in vivo and enhanced CpG immune adjuvant therapy by increasing dendritic cell activation and subsequent CD8(+) T-cell responses. Collectively, these data emphasize the crucial role of sialic acids in tumor immune evasion and provide proof of concept that sialic acid blockade creates an immune-permissive tumor microenvironment for CD8(+) T-cell-mediated tumor immunity, either as single treatment or in combination with other immune-based intervention strategies.Significance: Sialic acid sugars function as important modulators of the immunosuppressive tumor microenvironment that limit potent antitumor immunity.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3574/F1.large.jpg. (C) 2018 AACR.