Etablissement Français du Sang Auvergne-Rhône-Alpes, R&D Laboratory, Grenoble, France.
Institute for Advanced Biosciences, Team: Epigenetics, Immunity, Metabolism, Cell Signaling & Cancer, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
Front Immunol. 2022 Oct 24;13:1040600. doi: 10.3389/fimmu.2022.1040600. eCollection 2022.
Subversion of immunity by tumors is a crucial step for their development. Dendritic cells (DCs) are strategic immune cells that orchestrate anti-tumor immune responses but display altered functions in cancer. The bases for such DCs' hijacking are not fully understood. Tumor cells harbor unusual glycosylation patterns of surface glycoproteins and glycolipids. DCs express glycan-binding receptors, named C-type lectin receptors (CLR), allowing them to sense changes in glycan signature of their environment, and subsequently trigger a response. Recognition of tumor glycans by CLRs is crucial for DCs to shape antitumor immunity, and decisive in the orientation of the response. Yet the status of the CLR machinery on DCs in cancer, especially melanoma, remained largely unknown. We explored CLR expression patterns on circulating and tumor-infiltrating cDC1s, cDC2s, and pDCs of melanoma patients, assessed their clinical relevance, and further depicted the correlations between CLR expression profiles and DCs' features. For the first time, we highlighted that the CLR repertoire of circulating and tumor-infiltrating cDC1s, cDC2s, and pDCs was strongly perturbed in melanoma patients, with modulation of DCIR, CLEC-12α and NKp44 on circulating DCs, and perturbation of Dectin-1, CD206, DEC205, DC-SIGN and CLEC-9α on tumor-infiltrating DCs. Furthermore, melanoma tumor cells directly altered CLR expression profiles of healthy DC subsets, and this was associated with specific glycan patterns (Man, Fuc, GlcNAc) that may interact with DCs through CLR molecules. Notably, specific CLR expression profiles on DC subsets correlated with unique DCs' activation status and functionality and were associated with clinical outcome of melanoma patients. Higher proportions of DCIR-, DEC205-, CLEC-12α-expressing cDCs were linked with a better survival, whereas elevated proportions of CD206-, Dectin1-expressing cDCs and NKp44-expressing pDCs were associated with a poor outcome. Thus, melanoma tumor may shape DCs' features by exploiting the plasticity of the CLR machinery. Our study revealed that melanoma manipulates CLR pathways to hijack DC subsets and escape from immune control. It further paved the way to exploit glycan-lectin interactions for the design of innovative therapeutic strategies, which exploit DCs' potentialities while avoiding hijacking by tumor, to properly reshape anti-tumor immunity by manipulating the CLR machinery.
肿瘤对免疫的颠覆是其发展的关键步骤。树突状细胞（DCs）是一种战略性免疫细胞，能够协调抗肿瘤免疫反应，但在癌症中表现出改变的功能。这种 DC 劫持的基础尚未完全理解。肿瘤细胞具有表面糖蛋白和糖脂的异常糖基化模式。DC 表达糖结合受体，称为 C 型凝集素受体（CLR），使它们能够感知其环境中聚糖特征的变化，并随后触发反应。CLR 识别肿瘤糖基对于 DC 形成抗肿瘤免疫至关重要，并且对反应的方向具有决定性。然而，癌症中 DCs 上的 CLR 机制的状态，特别是黑色素瘤，仍然知之甚少。我们研究了黑色素瘤患者循环和肿瘤浸润性 cDC1s、cDC2s 和 pDCs 上的 CLR 表达模式，评估了它们的临床相关性，并进一步描述了 CLR 表达谱与 DCs 特征之间的相关性。我们首次强调，黑色素瘤患者的循环和肿瘤浸润性 cDC1s、cDC2s 和 pDCs 的 CLR 谱受到强烈干扰，循环 DC 上的 DCIR、CLEC-12α 和 NKp44 发生调节，肿瘤浸润性 DC 上的 Dectin-1、CD206、DEC205、DC-SIGN 和 CLEC-9α 受到干扰。此外，黑色素瘤肿瘤细胞直接改变了健康 DC 亚群的 CLR 表达谱，这与可能通过 CLR 分子与 DC 相互作用的特定糖基模式（Man、Fuc、GlcNAc）有关。值得注意的是，DC 亚群上的特定 CLR 表达谱与独特的 DC 激活状态和功能相关，并与黑色素瘤患者的临床结局相关。表达更高比例的 DCIR、DEC205、CLEC-12α 的 cDCs 与更好的生存相关，而表达更高比例的 CD206、Dectin1 的 cDCs 和表达 NKp44 的 pDCs 与较差的预后相关。因此，黑色素瘤肿瘤可能通过利用 CLR 机制的可塑性来塑造 DC 的特征。我们的研究表明，黑色素瘤通过利用 CLR 途径来劫持 DC 亚群并逃避免疫控制。它进一步为利用聚糖-凝集素相互作用来设计创新的治疗策略铺平了道路，这些策略利用了 DC 的潜力，同时避免了肿瘤的劫持，通过操纵 CLR 机制来正确重塑抗肿瘤免疫。
