Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer

contente

Mariluz Soula, Gokhan Unlu, Rachel Welch, Aleksey Chudnovskiy, Beste Uygur, Vyom Shah, Hanan Alwaseem, Paul Bunk, Vishvak Subramanyam, Hsi Wen Yeh, Artem Khan, Søren Heissel, Hani Goodarzi, Gabriel D. Victora, Semir Beyaz, Kıvanç Birsoy

Research output: Contribution to journal › Article › peer-review

  • Malignant Neoplasm Medicine and Dentistry 100%
  • Glycosphingolipid Medicine and Dentistry 100%
  • Immune Evasion Medicine and Dentistry 100%
  • Glycosphingolipids Keyphrases 100%
  • KRAS Biochemistry, Genetics and Molecular Biology 100%
  • Cell Surface Immunology and Microbiology 100%
  • Tumor Escape Immunology and Microbiology 100%
  • Tumor Progression Medicine and Dentistry 50%

Soula, M., Unlu, G., Welch, R., Chudnovskiy, A., Uygur, B., Shah, V., Alwaseem, H., Bunk, P., Subramanyam, V., Yeh, H. W., Khan, A., Heissel, S., Goodarzi, H., Victora, G. D., Beyaz, S., & Birsoy, K. (2024). Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer. Nature, 633(8029), 451-458. https://doi.org/10.1038/s41586-024-07787-1

@article{2b7b7503e4214f778f8f5b27c17a2790,

title = "Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer",

abstract = "Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.",

author = "Mariluz Soula and Gokhan Unlu and Rachel Welch and Aleksey Chudnovskiy and Beste Uygur and Vyom Shah and Hanan Alwaseem and Paul Bunk and Vishvak Subramanyam and Yeh, {Hsi Wen} and Artem Khan and S{\o}ren Heissel and Hani Goodarzi and Victora, {Gabriel D.} and Semir Beyaz and Kıvan{\c c} Birsoy",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2024.",

doi = "10.1038/s41586-024-07787-1",

publisher = "Nature Publishing Group",

}

Soula, M, Unlu, G, Welch, R, Chudnovskiy, A, Uygur, B, Shah, V, Alwaseem, H, Bunk, P, Subramanyam, V, Yeh, HW, Khan, A, Heissel, S, Goodarzi, H, Victora, GD, Beyaz, S & Birsoy, K 2024, 'Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer', Nature, vol. 633, no. 8029, pp. 451-458. https://doi.org/10.1038/s41586-024-07787-1

TY - JOUR

T1 - Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer

AU - Soula, Mariluz

AU - Unlu, Gokhan

AU - Welch, Rachel

AU - Chudnovskiy, Aleksey

AU - Uygur, Beste

AU - Shah, Vyom

AU - Alwaseem, Hanan

AU - Bunk, Paul

AU - Subramanyam, Vishvak

AU - Yeh, Hsi Wen

AU - Khan, Artem

AU - Heissel, Søren

AU - Goodarzi, Hani

AU - Victora, Gabriel D.

AU - Beyaz, Semir

AU - Birsoy, Kıvanç

N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer Nature Limited 2024.

PY - 2024/9/12

Y1 - 2024/9/12

N2 - Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.

AB - Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8+ T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.

UR - http://www.scopus.com/inward/record.url?scp=85200695959&partnerID=8YFLogxK

U2 - 10.1038/s41586-024-07787-1

DO - 10.1038/s41586-024-07787-1

M3 - Article

AN - SCOPUS:85200695959

SN - 0028-0836

VL - 633

SP - 451

EP - 458

JO - Nature

JF - Nature

IS - 8029

ER -

Resumir
这篇文章探讨了糖鞘脂合成在KRAS驱动的癌症免疫逃逸中的作用。研究表明,癌细胞通过改变脂质来适应环境,而糖鞘脂的合成是癌症免疫逃逸的关键途径。尽管糖鞘脂的合成对癌细胞在培养基或免疫缺陷小鼠中的增殖并非必需,但在多种同种异体模型中却是肿瘤生长所必需的。阻断糖鞘脂的生产可以增强自然杀伤细胞和CD8+ T细胞的抗增殖效果,部分通过干扰素-γ(IFNγ)信号通路实现。此外,糖鞘脂的耗竭会增加IFNγ受体亚单位1(IFNGR1)的表面水平,从而介导IFNγ诱导的生长停滞和促炎信号。最后,药理学抑制糖鞘脂合成与检查点阻断疗法协同作用,增强抗肿瘤免疫反应。总之,研究确认糖鞘脂是癌症免疫逃逸所需的重要代谢物。