Institute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling and Cancer, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
Etablissement Français du Sang Auvergne-Rhône-Alpes, R&D Laboratory, Grenoble, France.
Front Immunol. 2023 Feb 20;14:1120434. doi: 10.3389/fimmu.2023.1120434. eCollection 2023.
Subversion of immunity is a hallmark of cancer development. Dendritic cells (DCs) are strategic immune cells triggering anti-tumor immune responses, but tumor cells exploit their versatility to subvert their functions. Tumor cells harbor unusual glycosylation patterns, which can be sensed through glycan-binding receptors (lectins) expressed by immune cells that are crucial for DCs to shape and orientate antitumor immunity. Yet, the global tumor glyco-code and its impact on immunity has not been explored in melanoma. To decrypt the potential link between aberrant glycosylation patterns and immune evasion in melanoma, we investigated the melanoma tumor glyco-code through the GLYcoPROFILE™ methodology (lectin arrays), and depicted its impact on patients' clinical outcome and DC subsets' functionality. Specific glycan patterns correlated with clinical outcome of melanoma patients, GlcNAc, NeuAc, TF-Ag and Fuc motifs being associated with poor outcome, whereas Man and Glc residues elicited better survival. Strikingly, tumor cells differentially impacting cytokine production by DCs harbored distinct glyco-profiles. GlcNAc exhibited a negative influence on cDC2s, whereas Fuc and Gal displayed inhibitory impacts on cDC1s and pDCs. We further identified potential booster glycans for cDC1s and pDCs. Targeting specific glycans on melanoma tumor cells restored DCs' functionality. The tumor glyco-code was also linked to the nature of the immune infiltrate. This study unveils the impact of melanoma glycan patterns on immunity, and paves the way for innovative therapeutic options. Glycans/lectins interactions arise as promising immune checkpoints to rescue DCs from tumor' hijacking to reshape antitumor immunity and inhibit immunosuppressive circuits triggered by aberrant tumor glycosylation.
免疫逃避是癌症发展的一个标志。树突状细胞 (DCs) 是触发抗肿瘤免疫反应的战略免疫细胞，但肿瘤细胞利用其多功能性来颠覆它们的功能。肿瘤细胞具有异常的糖基化模式，可以通过免疫细胞表达的糖结合受体 (凝集素) 感知，这些受体对于 DC 形成和定向抗肿瘤免疫至关重要。然而，黑色素瘤中尚未探索全局肿瘤糖码及其对免疫的影响。为了解密黑色素瘤中异常糖基化模式与免疫逃逸之间的潜在联系，我们通过 GLYcoPROFILE™ 方法 (凝集素阵列) 研究了黑色素瘤肿瘤糖码，并描述了其对患者临床结局和 DC 亚群功能的影响。特定的糖基模式与黑色素瘤患者的临床结局相关，GlcNAc、NeuAc、TF-Ag 和 Fuc 基序与不良结局相关，而 Man 和 Glc 残基则与更好的生存相关。引人注目的是，肿瘤细胞对 DC 细胞因子产生的不同影响与不同的糖基谱相关。GlcNAc 对 cDC2s 产生负面影响，而 Fuc 和 Gal 对 cDC1s 和 pDCs 则显示出抑制作用。我们进一步鉴定了针对 cDC1s 和 pDCs 的潜在增强糖。针对黑色素瘤肿瘤细胞上的特定糖基恢复了 DC 的功能。肿瘤糖码还与免疫浸润的性质有关。这项研究揭示了黑色素瘤糖基模式对免疫的影响，并为创新的治疗选择铺平了道路。糖/凝集素相互作用作为有前途的免疫检查点出现，可使 DC 免受肿瘤劫持，重塑抗肿瘤免疫，并抑制由异常肿瘤糖基化触发的免疫抑制回路。
