Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer

Content

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 - Uyghur, 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 - White, 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 -

Link
https://scholars.mssm.edu/en/publications/glycosphingolipid-synthesis-mediates-immune-evasion-in-kras-drive#:~:text=Mechanistically%2C%20depletion%20of%20glycosphingolipids%20increases%20surface%20levels%20of,checkpoint%20blockade%20therapy%20to%20enhance%20anti-tumour%20immune%20response.
Summary
The article by Soula et al. (2024) explores the role of glycosphingolipid synthesis in immune evasion in KRAS-driven cancers. The researchers utilized functional genomics and lipidomic techniques to demonstrate that while sphingolipid synthesis is not essential for cancer cell proliferation in vitro or in immunodeficient mice, it is crucial for tumor growth in syngeneic models. Inhibiting sphingolipid production enhances the effectiveness of natural killer and CD8+ T cells, partly through interferon-γ (IFNγ) signaling. The study reveals that the depletion of glycosphingolipids increases the surface expression of IFNγ receptor subunit 1 (IFNGR1), which is linked to growth arrest and pro-inflammatory signaling. Furthermore, pharmacological inhibition of glycosphingolipid synthesis was found to work synergistically with checkpoint blockade therapy, improving anti-tumor immune responses. This research highlights glycosphingolipids as critical metabolites that facilitate immune evasion in cancer, suggesting potential therapeutic targets for enhancing cancer treatment efficacy.