PDF(Pubmed)
Abstract：
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.
摘要：
肿瘤对免疫力的颠覆是其发展的关键步骤。树突状细胞(DC)是战略免疫细胞,其协调抗肿瘤免疫应答,但在癌症中显示出改变的功能。这种DC劫持的依据尚未完全理解。肿瘤细胞具有表面糖蛋白和糖脂的异常糖基化模式。DC表达聚糖结合受体，命名为C型凝集素受体（CLR），让他们感知环境中聚糖特征的变化，并随后触发响应。通过CLR识别肿瘤聚糖对于DC形成抗肿瘤免疫至关重要，对反应的方向具有决定性意义。然而，癌症中DCs的CLR机制的地位，尤其是黑色素瘤，基本上是未知的。我们探索了循环和肿瘤浸润性cDC1s上的CLR表达模式，cDC2s，和黑色素瘤患者的pDC，评估了它们的临床相关性，并进一步描述了CLR表达谱与DC特征之间的相关性。第一次,我们强调了循环和肿瘤浸润性cDC1s的CLR库，cDC2s，黑色素瘤患者的pDC受到强烈干扰，与DCIR的调制，循环DC上的CLEC-12α和NKp44，Dectin-1，CD206，DEC205，DC-SIGN和CLEC-9α对肿瘤浸润性DC的扰动。此外，黑色素瘤肿瘤细胞直接改变健康DC亚群的CLR表达谱，这与特定的聚糖模式(男人，Fuc,GlcNAc）可能通过CLR分子与DC相互作用。值得注意的是,DC亚群的特异性CLR表达谱与独特的DC活化状态和功能相关,并与黑色素瘤患者的临床结局相关.较高比例的DCIR-，DEC205-,表达CLEC-12α的cDC与更好的存活率相关，而CD206-的比例升高，表达Dectin1的cDC和表达NKp44的pDC与不良结果相关。因此，黑色素瘤肿瘤可以通过利用CLR机制的可塑性来塑造DC的特征。我们的研究表明，黑色素瘤操纵CLR途径劫持DC亚群并逃避免疫控制。它进一步为利用聚糖-凝集素相互作用设计创新的治疗策略铺平了道路。它们利用DC的潜力，同时避免被肿瘤劫持，通过操纵CLR机制来正确重塑抗肿瘤免疫力。
