Fiche publication
Date publication
octobre 2021
Journal
Nature immunology
Auteurs
Membres identifiés du Cancéropôle Est :
Pr MASSON David
Tous les auteurs :
Di Conza G, Tsai CH, Gallart-Ayala H, Yu YR, Franco F, Zaffalon L, Xie X, Li X, Xiao Z, Raines LN, Falquet M, Jalil A, Locasale JW, Percipalle P, Masson D, Huang SC, Martinon F, Ivanisevic J, Ho PC
Lien Pubmed
Résumé
Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.
Référence
Nat Immunol. 2021 Oct 22;:
