IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies1. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leadingto dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in...

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Bibliographic Details
Published in:Nature (London) 2023-11, Vol.623 (7986), p.415-422
Main Authors: Caronni, Nicoletta, La Terza, Federica, Vittoria, Francesco M., Barbiera, Giulia, Mezzanzanica, Luca, Cuzzola, Vincenzo, Barresi, Simona, Pellegatta, Marta, Canevazzi, Paolo, Dunsmore, Garett, Leonardi, Carlo, Montaldo, Elisa, Lusito, Eleonora, Dugnani, Erica, Citro, Antonio, Ng, Melissa S. F., Schiavo Lena, Marco, Drago, Denise, Andolfo, Annapaola, Brugiapaglia, Silvia, Scagliotti, Alessandro, Mortellaro, Alessandra, Corbo, Vincenzo, Liu, Zhaoyuan, Mondino, Anna, Dellabona, Paolo, Piemonti, Lorenzo, Taveggia, Carla, Doglioni, Claudio, Cappello, Paola, Novelli, Francesco, Iannacone, Matteo, Ng, Lai Guan, Ginhoux, Florent, Crippa, Stefano, Falconi, Massimo, Bonini, Chiara, Naldini, Luigi, Genua, Marco, Ostuni, Renato
Format: Article
Language:English
Subjects:
Adenocarcinoma
Angiogenesis
Cancer
Cancer therapies
Cell cycle
Chemotherapy
Cytotoxicity
Disease resistance
Functionals
Genes
Genomics
High resistance
Immunomodulation
Inflammation
Macrophages
Medical prognosis
Pancreatic cancer
Prostaglandin E2
Tumor microenvironment
Tumor necrosis factor-TNF
Tumors
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Summary:Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies1. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leadingto dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC2, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-lß (IL-lß)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E2 (PGE2) and tumour necrosis factor (TNF). Physical proximity with 1L-Iß+TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatictumorigenesis and led to persistenttranscriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE2 or IL-lß activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leadingto PDAC control in vivo. Targetingthe PGE2-IL-lß axis may enable preventive ortherapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-023-06685-2