Nature immunology, 2021-11, Vol.22 (11), p.1403-1415
2021
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- Autor(en) / Beteiligte
- Titel
- Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity
- Ist Teil von
- Nature immunology, 2021-11, Vol.22 (11), p.1403-1415
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1529-2908eISSN: 1529-2916DOI: 10.1038/s41590-021-01047-4Titel-ID: cdi_pubmed_primary_34686867
- Format
- –
- Schlagworte
- Animals, Cell Line, Tumor, Cell Survival, Endoplasmic Reticulum - metabolism, Endoplasmic Reticulum - ultrastructure, Endoplasmic Reticulum Stress, Glucosylceramidase - metabolism, Intracellular Membranes - metabolism, Intracellular Membranes - ultrastructure, Macrophage Activation, Melanoma - genetics, Melanoma - metabolism, Melanoma - ultrastructure, Membrane Lipids - metabolism, Membrane Proteins - genetics, Membrane Proteins - metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Phosphorylation, Protein Serine-Threonine Kinases - genetics, Protein Serine-Threonine Kinases - metabolism, Skin Neoplasms - genetics, Skin Neoplasms - metabolism, Skin Neoplasms - ultrastructure, STAT3 Transcription Factor - genetics, STAT3 Transcription Factor - metabolism, Tumor Escape, Tumor Microenvironment, Tumor-Associated Macrophages - metabolism, Tumor-Associated Macrophages - ultrastructure, X-Box Binding Protein 1 - genetics, X-Box Binding Protein 1 - metabolism