As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach. We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level. We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition. Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC.

中文翻译：

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空间分辨多组学单细胞分析揭示胰腺癌免疫功能障碍的机制

由于胰腺导管腺癌 (PDAC) 仍然难以接受治疗干预，包括对免疫疗法反应不佳，尽管免疫疗法对其他实体恶性肿瘤有效，但迫切需要对 PDAC 中的免疫微环境有更细致的了解。我们的目标是使用空间分辨的多模式单细胞方法揭示 PDAC 中免疫微环境的详细视图。我们应用单细胞 RNA 测序、空间转录组学、多重免疫组织化学和质谱流式分析来分析未经治疗的 PDAC 肿瘤和匹配的邻近正常胰腺组织以及体循环中的免疫区室。我们确定了免疫特征的预后关联，并对 PDAC 和肺腺癌的单细胞水平的免疫微环境进行了荟萃分析。我们提供了 PDAC 中免疫景观的空间分辨精细图。我们证实了 CD8 T 细胞的耗竭表型和骨髓细胞的免疫抑制特征，并强调了在 PDAC 中可能被低估的免疫亚群，这些免疫亚群与邻近正常区域内的免疫群体不同，特别是最终耗竭的 CD4 T 细胞亚群和自然杀伤 T 细胞并获得调节表型。 PDAC 和肺腺癌免疫表型的差异分析揭示了 PDAC 中存在异常免疫抑制亚型以及独特的免疫检查点组成。我们的研究揭示了 PDAC 的多层免疫功能障碍，并提出了 PDAC 和肺腺癌免疫景观的整体视图，为 PDAC 的功能研究和治疗可行靶点的探索提供了全面的资源。