CCL3 Predicts Exceptional Response to TGFβ Inhibition in Basal-like Pancreatic Cancer Enriched in LIF-producing Macrophages

Overview

Journal NPJ Precis Oncol

Publisher Springer Nature

Specialty Oncology

Date 2024 Oct 31

PMID 39478186

Authors

Silvia Pietrobono

Monica Bertolini

Veronica De Vita

Fabio Sabbadini

Federica Fazzini

Cristina Frusteri

Enza Scarlato

Domenico Mangiameli

Alberto Quinzii

Simona Casalino

Camilla Zecchetto

Valeria Merz

Davide Melisi

Affiliations

Soon will be listed here.

Abstract

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.

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