Cancer cells rely on specific lipid pathways, such as sphingolipids, for growth and proliferation, leading to an upregulation of lipid synthesis. While it is established that an excess of lipids can promote metastasis and immune evasion in murine models, the specific types of lipids implicated in tumorigenesis remain inadequately defined. To elucidate which lipid pathways contribute to tumor formation, researchers conducted in vivo genetic assays.
Soula and colleagues conducted in vivo screens using a KRAS-mutant mouse pancreatic ductal adenocarcinoma (PDAC) cell line. They inoculated these KRAS-mutant PDAC cells into various mouse cohorts, including immunocompetent mice, myeloablative control mice, and NOD-SCID-γ (NSG) mice, which lack mature T, B, and natural killer (NK) cells. The growth of tumors in mice was assessed based on the calculated gene scores. Their results indicated that sphingolipid synthesis (a membrane lipid) is essential for immune evasion, particularly in immunocompetent mice compared to immunodeficient mice. This finding highlights the significance of sphingolipids in facilitating tumor immune evasion.
Sphingolipids are essential structural components of cell membranes and play a role in regulating cellular signal transduction and cell-cell interactions. They are synthesized in the endoplasmic reticulum by catalyzing with the enzyme called serine palmitoyl transferase (SPT). In the absence of the genes that encode this enzyme, sphingolipids couldn’t be synthesized. On SPT loss, tumor growth is debilitated in immunocompetent mice. SPT enzyme is crucial for tumor immune evasion, as its absence debilitates tumor growth in immunocompetent mice. The research team also explored the role of SPT in other cancer types, including liver and lung cancers. They observed that the loss of SPT disrupted tumor growth and extended survival in these models as well.
While sphingolipids cannot be synthesized without the SPT enzyme, they can be sourced from exogenous sources to produce new lipids. The study concluded that although exogenous sphingolipids support cell proliferation, de novo synthesis of sphingolipids is necessary for effective immune evasion.
To identify how sphingolipid depletion can change the effects of immune cells on cancer cells, they analyzed the regulation of NK and CD8+ T cells in SPT-depleted tumor cells and SPT-including tumor cells. According to the results, increased activation of immune cells is observed in SPT-depleted tumors which means in the absence of sphingolipids, tumor cells are more sensitive to the anti-proliferative effects of NK cells. NK cells secrete cytokines like IFN-γ (interferon gamma) triggering pro-inflammatory signaling through the JAK-STAT interferon signaling pathway. This enhances immune cell activation, particularly in SPT-depleted tumors.
The scientist also established that there are alterations when plasma membrane proteins are also isolated from SPT-depleted cancer cells. The researchers found that there are significant changes in the amount of membrane proteins: the proteins such as IFNGR1 and the ones related to endocytosis were upregulated in the loss of sphingolipid synthesis in tumors. The loss of sphingolipid synthesis also causes increased IFNGR1 surface expression. Besides that, this increase is sustained when there is IFN-γ stimulation. When investigating which lipid species influence IFNGR1 levels, the researchers found that the UDP-glucose ceramide glucosyltransferase (Ugcg) gene, which catalyzes the conversion of ceramide into glycosphingolipids, plays a critical role in mediating IFNGR1 surface expression. The loss of Ugcg leads to a reduction in glycosphingolipids, which in turn increases sensitivity to IFN-γ and results in an overall impairment of tumor growth.
In conclusion, the study reveals that targeting membrane sphingolipid composition through the inhibition of Ugcg with eliglustat significantly improves the response of KRAS-driven cancer cells to immunotherapy. The combination of eliglustat and checkpoint blockade therapy (CBT) enhances sensitivity to IFN-γ-induced growth arrest, highlighting a novel approach to overcoming immune resistance in tumors. This finding suggests that manipulating sphingolipid levels can be a promising strategy to bolster the efficacy of existing immunotherapeutic modalities. The research underscores the potential of sphingolipid modulation as a therapeutic adjunct in the treatment of KRAS-mutant cancers, offering a new avenue for enhancing immune checkpoint therapies. However, further investigation is required to determine whether this approach can be generalized to other cancer types beyond KRAS-driven tumors. Future studies should explore the applicability of sphingolipid-targeted therapies in a broader range of malignancies and evaluate the long-term impact on treatment outcomes and patient survival.
Yazar: Ebrar Yolcu
Editör: Elif Duymaz
Reference: Soula, M., Unlu, G., Welch, R., Chudnovskiy, A., Uygur, B., Shah, V., Alwaseem, H., Bunk, P., Subramanyam, V., Yeh, H., Khan, A., Heissel, S., Goodarzi, H., Victora, G. D., Beyaz, S., & Birsoy, K. (2024). Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer. Nature. https://doi.org/10.1038/s41586-024-07787-1
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