CCL3 predicts exceptional response to TGFβ inhibition in basal-like pancreatic cancer enriched in LIF-producing macrophages

• Published in: NPJ precision oncology Vol. 8; no. 1; pp. 246 - 15
• Main Authors: Pietrobono, Silvia, Bertolini, Monica, De Vita, Veronica, Sabbadini, Fabio, Fazzini, Federica, Frusteri, Cristina, Scarlato, Enza, Mangiameli, Domenico, Quinzii, Alberto, Casalino, Simona, Zecchetto, Camilla, Merz, Valeria, Melisi, Davide
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-10-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/67/1059/602; 692/4028/67/1504/1713; 692/53/2423; Biomarkers; Cancer Research; Cancer therapies; Chemokines; Gene Therapy; Human Genetics; Internal Medicine; Medical prognosis; Medicine; Medicine & Public Health; Metastasis; Oncology; Pancreatic cancer; Signal transduction; Tumors
• ISSN: 2397-768X; 2397-768X
• DOI: 10.1038/s41698-024-00742-3

The TGFβ receptor inhibitor galunisertib showed promising efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the phase 2 H9H-MC-JBAJ study. Identifying biomarkers for this treatment remains essential. Baseline plasma levels of chemokine CCL3 were integrated with clinical outcomes in PDAC patients treated with galunisertib plus gemcitabine (
n
 = 104) or placebo plus gemcitabine (
n
 = 52). High CCL3 was a poor prognostic factor in the placebo group (mOS 3.6 vs. 10.1 months;
p
 < 0.01) but a positive predictor for galunisertib (mOS 9.2 vs. 3.6 months;
p
 < 0.01). Mechanistically, tumor-derived CCL3 activates Tgfβ signaling in macrophages, inducing their M2 phenotype and Lif secretion, sustaining a mesenchymal/basal-like ecotype. TGFβ inhibition redirects macrophage polarization to M1, reducing Lif and shifting PDAC cells to a more epithelial/classical phenotype, improving gemcitabine sensitivity. This study supports exploring TGFβ-targeting agents in PDAC with a mesenchymal/basal-like ecotype driven by high CCL3 levels.