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Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer

ABSTRACT: Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer

PROVIDER: PRJNA1127642 | ENA |

REPOSITORIES: ENA

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Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer

Project description:Cancer cells frequently alter their lipids to grow and adapt to their environment1–3. Despite the critical functions of lipid metabolism in membrane physiology, signaling, and energy production, how specific lipids contribute to tumorigenesis is 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 tumor growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer (NK) and CD8+ T cells partly via interferon gamma (IFNg) signaling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNg receptor subunit 1 (Ifngr1), mediating IFNg-induced growth arrest and proinflammatory signaling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumor immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.

2024-06-30 | GSE270660 | GEO

Glycosphingolipid synthesis mediates immune evasion in Kras-driven cancer

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cAMP response element-binding protein mediates immune-evasion of KRAS-mutant lung adenocarcinomas

Project description:We discovered that KRAS-mutant lung adenocarcinomas (LADC) co-opt CREB in order to evade the innate immune system: KRAS-driven CREB activation in LADC suppresses the expression of CXCR1 ligands that would otherwise recruit neutrophils to the tumor site. CREB was overexpressed in murine KRAS-mutant LADC, pulmonary Creb1-deletion inhibited disease development, and Creb1-overexpression boosted the tumorigenicity of KRAS-mutant cells. Conditional Creb1 deletion in Kras-mutant LADC cells caused overexpression of CXCR1/2 ligands, and lung tumor-bearing Creb1-deleted mice displayed increased pulmonary neutrophils. Cxcr1-deficient mice were selectively permissive to KRAS-mutant tumor growth and showed defective neutrophil recruitment. The pro-tumor effects of CREB required intact host-Cxcr1 and those of host-Cxcr1 necessitated mutant KRAS in cancer cells. Pharmacologic CREB blockade prevented tumor growth and restored neutrophil recruitment only when initiated before immune evasion of KRAS-mutant LADC cells. CREB and CXCR1 expression were respectively restricted to tumor and stromal cells of human LADC, while CREB-controlled genes profoundly impacted survival. In summary, CREB-mediated immune evasion of KRAS-mutant LADC rests on signaling to myeloid CXCR1 and is actionable.

2023-08-19 | GSE156513 | GEO

cAMP response element-binding protein mediates immune-evasion of KRAS-mutant lung adenocarcinomas

Project description:cAMP response element-binding protein mediates immune-evasion of KRAS-mutant lung adenocarcinomas

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KRAS drives immune evasion in a genetic model of pancreatic cancer [bulk RNA-seq]

Project description:Immune evasion is a hallmark of KRAS-driven cancers, but underlying mechanism and clinical implications remain unclear.

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KRAS drives immune evasion in a genetic model of pancreatic cancer

Project description:We used CRISPR/Cas9 genome editing to inactivate KRAS in pancreatic cancer cells and isolated cell populations that still produce tumors in mice. We show that the malignant phenotype of KRAS knockout cells is stable. However, KRAS deficient cancer cells fail to avoid detection and elimination by the host immune system, indicating that a key aspect of tumor maintenance by oncogenic KRAS is to promote immune evasion. Our study uncovers changes both in cancer cells and stromal immunoreactive cells attributable to KRAS expression. Complementation studies indicate that BRAF, AKT and MYC are causative drivers of KRAS-mediated immune suppression. These results show that combination treatments that both target KRAS signaling and boost antitumor immunity will be an effective strategy to treat PDAC.

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