Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer

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. Using a spatially-resolved multimodal single cell approach we unveil a detailed view of the immune micromilieu in PDAC with specific emphasis on the correlation of immune subtypes with patient prognosis. We substantiate the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlight immune subpopulations with potentially underappreciated roles in PDAC that diverge from immune populations within adjacent normal areas, particularly CD4 T cell subsets presenting immunosuppressive phenotypes with varying modes of exhaustion. We reveal striking differences between immune phenotypes in PDAC and lung adenocarcinoma, which explain their differential responsiveness to current immunotherapies, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC. mRNA profiles of 9 PDAC and paired adjacent tissues

尽管免疫治疗在其他实体恶性肿瘤中疗效确切，但胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）仍对包括免疫治疗在内的多种治疗手段存在抵抗且应答不佳，因此亟需对PDAC的免疫微环境展开更为细致深入的解析。本研究采用空间分辨多模态单细胞技术，清晰刻画了PDAC的免疫微环境细节，并重点聚焦免疫亚型与患者预后的关联关系。研究证实了CD8+ T细胞的耗竭表型与髓系细胞的免疫抑制特性，并揭示了PDAC中部分免疫亚群与邻近正常组织内的免疫群体存在显著差异，这些亚群在PDAC中可能发挥着此前未被充分认知的作用，其中尤以呈现不同耗竭模式的免疫抑制性CD4+ T细胞亚群最为突出。本研究还发现，PDAC与肺腺癌的免疫表型存在显著差异，这一发现可解释二者对当前免疫治疗应答的差异性，并为PDAC的功能研究以及治疗靶点的探索提供了一套全面的研究资源。本数据集包含9例PDAC组织及其配对邻近正常组织的mRNA表达谱。