Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion
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PROVIDER: PRJNA1136969 | ENA |
REPOSITORIES: ENA
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Project description:B7-H4 functions as an immune checkpoint in the tumor microenvironment (TME). However, the post-translational modification (PTM) of B7-H4 and its translational potential in cancer remains incompletely understood. We found that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4-mediated immunosuppression. Knockdown of ZDHHC3 in tumors resulted in robust anti-tumor immunity and reduced tumor progression in murine models. Moreover, abemaciclib, a CDK4/6 inhibitor, primed lysosome activation and promoted lysosomal degradation of B7-H4 independently of the tumor cell cycle. Treatment with abemaciclib resulted in T cell activation and mitigated B7-H4-mediated immune suppression via inducing B7-H4 degradation in preclinical tumor models. Thus, B7-H4 palmitoylation is an undocumented PTM controlling B7-H4 protein stability and abemaciclib may be repurposed to enhance B7-H4 degradation, thereby treating patients with B7-H4+ tumors.
2025-02-14 | PXD054393 | Pride
Project description:To investigate the function of CDK4/6 inhibitor- Abemaciclib on lysosome function.
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Project description:The goal of this study are to find the abonormally expressed genes of B7-H4-/- leukemia inital cells in MLL-AF9 induced AML mice by RNA-seq analysis.Methods: Lin- festival liver cells were isolated from WT and B7-H4-null mice and infected with MLL-AF9 retroviruses, then transplanted to the lethally irradiated recipient mice. When AML developed, we isolated the YFP+/Mac-1+/c-Kit+ bone marrow cells by FACS and and then made the RNA-sequence using Illumina. Results: We identified 27180 transcripts in wild type and B7-H4-/- leukemia initial cells. 572 transcripts showed differential expression between the WT and B7-H4−/− LICs, with a fold change ≥1.5 and p value <0.01. 271 transcripts were downregulated and 241 transcripts were upregulated.
2018-10-25 | GSE89161 | GEO
Project description:Chronic islet inflammation is a hallmark of type 2 diabetes (T2D) and involves in the dysfunction of β cells. However, how β cells participate in this process remains unclear. Here, we report that the immune checkpoint molecule B7-H4(B7S1, B7x, VTCN1) expressed in β cells is critical to maintain β cell mass and insulin secretion. Lesion of B7-H4 in β cells results in glucose intolerance due to less β cell mass and deficient insulin secretion with upregulated cytokines and activated signal transducer and activator of transcription 5 (Stat5) signaling, while overexpression of B7-H4 in β cells ameliorates glucose intolerance in high-fat diet (HFD)-treated mice. Mechanistically, B7-H4 deficiency actives the Stat5 signaling, which inhibits the expression of Apolipoprotein F (ApoF), leading to reduced cholesterol efflux and accumulated cholesterol in β cells, thereby impairing the insulin processing and secretion. Inhibiting Stat5 activity or overexpression of ApoF in β cells can rescue the glucose intolerance and insulin secretion deficiency in β-cell-specific B7-H4 knockout (B7-H4 cKO) mice. Our study demonstrates that β cell expressed immune checkpoint molecule B7-H4 is essential for islet immune homeostasis and β cell function maintenance, and for the first time unravels the mechanism by which B7-H4 regulates insulin secretion through regulating cholesterol metabolism via Stat5 signaling, which may shed new light on the development of novel strategies for T2D treatment.
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Project description:Analysis of mouse ovarian cancer cell lines HM-1 and ID8, and HM-1 tumors inoculated to B6C3F1 mice with B7-H3 (Cd276) knockout (KO) by CRISPR-Cas9. We identified B7-H3 expression is upregulated in IFN-γ–low, PD-L1–low non-immunoreactive tumors of high grade serous ovarian cancer. We explored the influence of B7-H3 on immune evasion outside of its direct regulatory function on target cells by generating B7-H3 knockout cell lines and tumors in syngeneic mouse models.
2022-01-10 | GSE174137 | GEO
Project description:Post-translational modifications of malignant transformation and tumor maintenance in pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remains largely unexplored. Here, we used the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits lysosomal localization and degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we designed a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulated MYC expression and inhibited the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20-YTHDF3-MYC signaling axis in pancreatic cancer.
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