IL-1b+ tumor-associated macrophages fuel pathogenic inflammation in pancreatic cancer - Molecular Cartography of human PDAC samples

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapy. Inflammatory and immunomodulatory signals co-exist in the tumor microenvironment (TME), leading to dysregulated reparative and cytotoxic responses. Tumor-associated macrophages (TAMs) control immune dynamics in the TME, but their heterogeneity and plasticity have hampered understanding of the underlying mechanisms. Here, we combined single-cell and spatial genomics with functional experiments to elucidate macrophage functions in PDAC. We uncovered an inflammatory loop between tumor cells and interleukin (IL)-1b+ TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2 (PGE2) and tumor necrosis factor (TNF)-a. Interfering with the PGE2-IL-1b axis elicited TAM reprogramming and antagonized tumor-intrinsic inflammation, leading to PDAC control in vivo. IL-1b+ TAMs are conserved across human cancers and correlate with inflammation and patient prognosis in a context-dependent manner. Our study highlights how TAMs govern between inflammation and immune suppression in cancer, with significant therapeutic implications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237846 | GEO | 2023/09/11

REPOSITORIES: GEO