Proton irradiation orchestrates macrophage reprogramming through NFκB signaling

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Abstract

Tumor-associated macrophages (TAMs) represent potential targets for anticancer treatments as these cells play critical roles in tumor progression and frequently antagonize the response to treatments. TAMs are usually associated to an M2-like phenotype, characterized by anti-inflammatory and protumoral properties. This phenotype contrasts with the M1-like macrophages, which exhibits proinflammatory, phagocytic, and antitumoral functions. As macrophages hold a high plasticity, strategies to orchestrate the reprogramming of M2-like TAMs towards a M1 antitumor phenotype offer potential therapeutic benefits. One of the most used anticancer treatments is the conventional X-ray radiotherapy (RT), but this therapy failed to reprogram TAMs towards an M1 phenotype. While protontherapy is more and more used in clinic to circumvent the side effects of conventional RT, the effects of proton irradiation on macrophages have not been investigated yet. Here we showed that M1 macrophages (THP-1 cell line) were more resistant to proton irradiation than unpolarized (M0) and M2 macrophages, which correlated with differential DNA damage detection. Moreover, proton irradiation-induced macrophage reprogramming from M2 to a mixed M1/M2 phenotype. This reprogramming required the nuclear translocation of NFκB p65 subunit as the inhibition of IκBα phosphorylation completely reverted the macrophage re-education. Altogether, the results suggest that proton irradiation promotes NFκB-mediated macrophage polarization towards M1 and opens new perspectives for macrophage targeting with charged particle therapy.

Original languageEnglish
Article number728
Number of pages13
JournalCell Death and Disease
Volume9
Issue number7
DOIs
Publication statusPublished - 27 Jun 2018

Keywords

  • Cell Nucleus/metabolism
  • Cellular Reprogramming/radiation effects
  • Histones/metabolism
  • Humans
  • Macrophages/metabolism
  • NF-kappa B/metabolism
  • Protein Transport
  • Protons
  • Radiation Tolerance/radiation effects
  • Signal Transduction
  • THP-1 Cells
  • Transcription Factor RelA/metabolism
  • Tumor Suppressor p53-Binding Protein 1/metabolism

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  • Equipment

  • Morphology - Imaging

    Charles Nicaise (Manager) & Francesca Cecchet (Manager)

    Technological Platform Morphology - Imaging

    Facility/equipment: Technological Platform

  • Student Theses

    Unravelling the effects of proton irradiation on macrophages in cancer

    Author: Genard, G., 30 May 2018

    Supervisor: Michiels, C. (Supervisor), Heuskin, A. (President), Lucas, S. (Jury), Poumay, Y. (Jury), Feron, O. (Jury) & Huber, P. E. (External person) (Jury)

    Student thesis: Doc typesDoctor of Sciences

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