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. Overall design: mRNA profiles of 9 PDAC and paired adjacent tissues