Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer.
IF: 33.883


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.


Spatial Transcriptomics
Lung Cancer
Pancreatic Cancer
Single-Cell Multi-Omics
Tumor Immunology

MeSH terms

Pancreatic Neoplasms
Carcinoma, Pancreatic Ductal
Immune System Diseases
Adenocarcinoma of Lung
Single-Cell Analysis
Tumor Microenvironment
Pancreatic Neoplasms


Yousuf, Suhail
Qiu, Mengjie
Voith von Voithenberg, Lena
Hulkkonen, Johannes
Macinkovic, Igor
Schulz, Axel R
Hartmann, Domenic
Mueller, Florian
Mijatovic, Margarete
Ibberson, David
AlHalabi, Karam T
Hetzer, Jenny
Anders, Simon
Brüne, Bernhard
Mei, Henrik E
Imbusch, Charles D
Brors, Benedikt
Heikenwälder, Mathias
Gaida, Matthias M
Büchler, Markus W
Weigert, Andreas
Hackert, Thilo
Roth, Susanne