PDF(Pubmed)
Abstract：
Conventional type 1 dendritic cells (cDC1) are critical regulators of anti-tumoral T-cell responses. The structure and abundance of intercellular contacts between cDC1 and CD8 T cells in cancer tissues is important to determine the outcome of the T-cell response. However, the molecular determinants controlling the stability of cDC1-CD8 interactions during cancer progression remain poorly investigated. Here, we generated a genetic model of non-small cell lung cancer crossed to a fluorescent cDC1 reporter (KP-XCR1venus) to allow the detection of cDC1-CD8T cell clusters in tumor tissues across tumor stages. We found that cDC1-CD8 clusters are abundant and productive at the early stages of tumor development but progressively diminish in advanced tumors. Transcriptional profiling and flow cytometry identified the adhesion molecule ALCAM/CD166 (Activated Leukocyte Cell Adhesion Molecule, ligand of CD6) as highly expressed by lung cDC1 and significantly downregulated in advanced tumors. Analysis of human datasets indicated that ALCAM is downregulated in non-small cell lung cancer and its expression correlates to better prognosis. Mechanistically, triggering ALCAM on lung cDC1 induces cytoskeletal remodeling and contact formation whereas its blockade prevents T-cell activation. Together, our results indicate that ALCAM is important to stabilize cDC1-CD8 interactions at early tumor stages, while its loss in advanced tumors contributes to immune evasion.
摘要：
常规的1型树突状细胞(cDC1)是抗肿瘤T细胞应答的关键调节因子。癌组织中cDC1和CD8T细胞之间的细胞间接触的结构和丰度对于确定T细胞应答的结果是重要的。然而,在癌症进展过程中控制cDC1-CD8相互作用稳定性的分子决定簇仍未得到充分研究.这里,我们建立了一个非小细胞肺癌的遗传模型,该模型与荧光cDC1报告基因(KP-XCR1venus)交叉,以允许在不同肿瘤分期的肿瘤组织中检测cDC1-CD8T细胞簇.我们发现cDC1-CD8簇在肿瘤发展的早期阶段是丰富和有生产力的，但在晚期肿瘤中逐渐减少。转录谱分析和流式细胞术鉴定了粘附分子ALCAM/CD166（活化的白细胞粘附分子，CD6的配体）在肺cDC1中高度表达，在晚期肿瘤中显着下调。对人类数据集的分析表明，ALCAM在非小细胞肺癌中下调，其表达与更好的预后相关。机械上,在肺cDC1上触发ALCAM诱导细胞骨架重塑和接触形成，而其阻断阻止T细胞活化。一起,我们的结果表明，ALCAM是重要的稳定cDC1-CD8相互作用在早期肿瘤阶段，而其在晚期肿瘤中的损失有助于免疫逃避。
