IL-1b+ tumor-associated macrophages fuel pathogenic inflammation in pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumor microenvironment (TME), leading to dysregulated repair and cytotoxic responses. Tumor-associated macrophages (TAMs) are key players in PDAC, but their diversity prevented therapeutic exploitation. Here, we combined single-cell and spatial genomics with functional experiments to elucidate macrophage functions in pancreatic cancer. 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. Physical proximity with IL-1B+ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor patient outcome. Blocking PGE2 or IL-1B elicited TAM reprogramming and antagonized tumor cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE2-IL-1B axis may enable preventive or therapeutic strategy to reprogramming of immune dynamics in pancreatic cancer.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE217847 | GEO | 2023/09/07

REPOSITORIES: GEO