Tumor-induced Reshuffling of Lipid Composition on the Endoplasmic Reticulum Membrane Sustains Macrophage Survival and Pro-tumorigenic Activity

Overview

Journal Nat Immunol

Date 2021 Oct 23

PMID 34686867

Citations 69

Authors

Giusy Di Conza

Chin-Hsien Tsai

Hector Gallart-Ayala

Yi-Ru Yu

Fabien Franco

Lea Zaffalon

Xin Xie

Xiaoyun Li

Zhengtao Xiao

Lydia N Raines

Maryline Falquet

Antoine Jalil

Jason W Locasale

Piergiorgio Percipalle

David Masson

Stanley Ching-Cheng Huang

Fabio Martinon

Julijana Ivanisevic

Ping-Chih Ho

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution.

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References

Lopez-Yrigoyen M, Cassetta L, Pollard J . Macrophage targeting in cancer. Ann N Y Acad Sci. 2020; 1499(1):18-41. DOI: 10.1111/nyas.14377. View

Loke P, Allison J . PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A. 2003; 100(9):5336-41. PMC: 154346. DOI: 10.1073/pnas.0931259100. View

Laoui D, Van Overmeire E, Di Conza G, Aldeni C, Keirsse J, Morias Y . Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. Cancer Res. 2013; 74(1):24-30. DOI: 10.1158/0008-5472.CAN-13-1196. View

Qian B, Pollard J . Macrophage diversity enhances tumor progression and metastasis. Cell. 2010; 141(1):39-51. PMC: 4994190. DOI: 10.1016/j.cell.2010.03.014. View

Wenes M, Shang M, Di Matteo M, Goveia J, Martin-Perez R, Serneels J . Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis. Cell Metab. 2016; 24(5):701-715. DOI: 10.1016/j.cmet.2016.09.008. View

Casazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M . Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell. 2013; 24(6):695-709. DOI: 10.1016/j.ccr.2013.11.007. View

Pyonteck S, Akkari L, Schuhmacher A, Bowman R, Sevenich L, Quail D . CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013; 19(10):1264-72. PMC: 3840724. DOI: 10.1038/nm.3337. View

Topper M, Vaz M, Chiappinelli K, DeStefano Shields C, Niknafs N, Yen R . Epigenetic Therapy Ties MYC Depletion to Reversing Immune Evasion and Treating Lung Cancer. Cell. 2017; 171(6):1284-1300.e21. PMC: 5808406. DOI: 10.1016/j.cell.2017.10.022. View

Liu Y, Liang X, Dong W, Fang Y, Lv J, Zhang T . Tumor-Repopulating Cells Induce PD-1 Expression in CD8 T Cells by Transferring Kynurenine and AhR Activation. Cancer Cell. 2018; 33(3):480-494.e7. DOI: 10.1016/j.ccell.2018.02.005. View

10.

Li X, Wenes M, Romero P, Huang S, Fendt S, Ho P . Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 2019; 16(7):425-441. DOI: 10.1038/s41571-019-0203-7. View

11.

Vriens K, Christen S, Parik S, Broekaert D, Yoshinaga K, Talebi A . Evidence for an alternative fatty acid desaturation pathway increasing cancer plasticity. Nature. 2019; 566(7744):403-406. PMC: 6390935. DOI: 10.1038/s41586-019-0904-1. View

12.

Chen M, Zhang J, Sampieri K, Clohessy J, Mendez L, Gonzalez-Billalabeitia E . An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer. Nat Genet. 2018; 50(2):206-218. PMC: 6714980. DOI: 10.1038/s41588-017-0027-2. View

13.

Wang H, Franco F, Tsui Y, Xie X, Trefny M, Zappasodi R . CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol. 2020; 21(3):298-308. PMC: 7043937. DOI: 10.1038/s41590-019-0589-5. View

14.

Herber D, Cao W, Nefedova Y, Novitskiy S, Nagaraj S, Tyurin V . Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med. 2010; 16(8):880-6. PMC: 2917488. DOI: 10.1038/nm.2172. View

15.

Veglia F, Tyurin V, Blasi M, De Leo A, Kossenkov A, Donthireddy L . Fatty acid transport protein 2 reprograms neutrophils in cancer. Nature. 2019; 569(7754):73-78. PMC: 6557120. DOI: 10.1038/s41586-019-1118-2. View

16.

Chen X, Cubillos-Ruiz J . Endoplasmic reticulum stress signals in the tumour and its microenvironment. Nat Rev Cancer. 2020; 21(2):71-88. PMC: 7927882. DOI: 10.1038/s41568-020-00312-2. View

17.

Song M, Sandoval T, Chae C, Chopra S, Tan C, Rutkowski M . IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature. 2018; 562(7727):423-428. PMC: 6237282. DOI: 10.1038/s41586-018-0597-x. View

18.

Ma X, Bi E, Lu Y, Su P, Huang C, Liu L . Cholesterol Induces CD8 T Cell Exhaustion in the Tumor Microenvironment. Cell Metab. 2019; 30(1):143-156.e5. PMC: 7061417. DOI: 10.1016/j.cmet.2019.04.002. View

19.

Cubillos-Ruiz J, Silberman P, Rutkowski M, Chopra S, Perales-Puchalt A, Song M . ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis. Cell. 2015; 161(7):1527-38. PMC: 4580135. DOI: 10.1016/j.cell.2015.05.025. View

20.

Mohamed E, Sierra R, Trillo-Tinoco J, Cao Y, Innamarato P, Payne K . The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling. Immunity. 2020; 52(4):668-682.e7. PMC: 7207019. DOI: 10.1016/j.immuni.2020.03.004. View