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Original article
Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy
  1. Giuseppe Di Caro1,
  2. Nina Cortese1,
  3. Giovanni Francesco Castino1,
  4. Fabio Grizzi1,
  5. Francesca Gavazzi2,
  6. Cristina Ridolfi2,
  7. Giovanni Capretti2,
  8. Rossana Mineri3,
  9. Jelena Todoric4,
  10. Alessandro Zerbi2,
  11. Paola Allavena1,
  12. Alberto Mantovani1,
  13. Federica Marchesi1
  1. 1Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Rozzano, Italy
  2. 2Section of Pancreatic Surgery, Department of Surgery, Humanitas Clinical and Research Center, Rozzano, Italy
  3. 3Molecular Biology Section, Clinical Investigation Laboratory, Humanitas Clinical and Research Center, Rozzano, Italy
  4. 4Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, San Diego, California, USA
  1. Correspondence to Dr Federica Marchesi, Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, Rozzano (MI) 20089, Italy; federica.marchesi{at}humanitasresearch.it

Abstract

Objective Tumour-associated macrophages (TAMs) play key roles in tumour progression. Recent evidence suggests that TAMs critically modulate the efficacy of anticancer therapies, raising the prospect of their targeting in human cancer.

Design In a large retrospective cohort study involving 110 patients with pancreatic ductal adenocarcinoma (PDAC), we assessed the density of CD68-TAM immune reactive area (%IRA) at the tumour–stroma interface and addressed their prognostic relevance in relation to postsurgical adjuvant chemotherapy (CTX). In vitro, we dissected the synergism of CTX and TAMs.

Results In human PDAC, TAMs predominantly exhibited an immunoregulatory profile, characterised by expression of scavenger receptors (CD206, CD163) and production of interleukin 10 (IL-10). Surprisingly, while the density of TAMs associated to worse prognosis and distant metastasis, CTX restrained their protumour prognostic significance. High density of TAMs at the tumour–stroma interface positively dictated prognostic responsiveness to CTX independently of T-cell density. Accordingly, in vitro, gemcitabine-treated macrophages became tumoricidal, activating a cytotoxic gene expression programme, inhibiting their protumoural effect and switching to an antitumour phenotype. In patients with human PDAC, neoadjuvant CTX was associated to a decreased density of CD206+ and IL-10+ TAMs at the tumour–stroma interface.

Conclusions Overall, our data highlight TAMs as critical determinants of prognostic responsiveness to CTX and provide clinical and in vitro evidence that CTX overall directly re-educates TAMs to restrain tumour progression. These results suggest that the quantification of TAMs could be exploited to select patients more likely to respond to CTX and provide the basis for novel strategies aimed at re-educating macrophages in the context of CTX.

  • PANCREATIC CANCER
  • MACROPHAGES
  • CHEMOTHERAPY
  • IMMUNOREGULATION
  • IMMUNOHISTOCHEMISTRY

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