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Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [Caprin-1 RNA-IP-seq]

ABSTRACT: Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [Caprin-1 RNA-IP-seq]

PROVIDER: PRJNA1054982 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27294708_1.fastq.gz	Fastqsanger.gz
	SRR27294708_2.fastq.gz	Fastqsanger.gz
	SRR27294709_1.fastq.gz	Fastqsanger.gz
	SRR27294709_2.fastq.gz	Fastqsanger.gz
	SRR27294710_1.fastq.gz	Fastqsanger.gz

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Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [EXOSC10 RNA-IP-seq]

Project description:Programmed death-ligand 1, PD-L1 (CD274), is expressed by cancer cells to facilitate immune evasion. PD-L1 also exerts pro-survival functions in cancer cells, and mechanisms that regulate intracellular PD-L1 signaling remain largely unknown. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF-b-receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), which are highly resistant to immunotherapy. Mechanistically, we show here that internalized PD-L1, mediated by its cytoplasmic domain, including the S278/S279 residues, in response to CerS4/C18/C20-ceramide downregulation or genetic loss, interacts with an RNA-binding protein Caprin-1 in various metastatic breast cancer models, including 4T1 orthotopic breast allografts and mammary tumors developed in MMTV-PyMT/CerS4-/- compared to MMTV-PyMT/CerS4+/+ mice, consistent with Shh/TGFBR1/Wnt/b-catenin activation in-vivo. Genetic loss or molecular knockdown of CerS4 in breast tumors also resulted in increased infiltration of FoxP3+ T regs that are known to suppress anti-tumor immunity. Targeting the CerS4/Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody in mice containing metastatic breast tumors in which CerS4 is downregulated vastly decreased tumor growth and metastasis, leading to inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and multiple patient datasets, demonstrate a mechanism to define intracellular metastatic signaling by PD-L1 internalization in response to alterations of ceramide metabolism, providing a new therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

2024-07-07 | GSE250638 | GEO

Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [Caprin-1 RNA-IP-seq]

2024-07-07 | GSE250637 | GEO

Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

Project description:Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

2025-05-07 | PXD053108 | Pride

Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

Project description:Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

2024-07-07 | GSE267312 | GEO

Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [EXOSC10 RNA-IP-seq]

Project description:Lipid Metabolism Alterations Induce PD-L1 Internalization and Signaling to Regulate Breast Cancer Metastasis and Response to Immunotherapy [EXOSC10 RNA-IP-seq]

| PRJNA1054984 | ENA

Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

Project description:Alterations of Ceramide Synthesis Induce PD-L1 Internalization and Signaling to Regulate Tumor Metastasis and Immunotherapy Response

| PRJNA1111042 | ENA

Branched N-glycan of PD-L1 predicts immunotherapy responses in patients with recurrent/metastatic HNSCC

Project description:Immunotherapy has revolutionized cancer treatment, however, a reliable biomarker is missing. MGAT5-mediated PD-L1 glycosylation is critical for its interaction with PD-1. MGAT5 expression is a functional biomarker that predicts immunotherapy responses.

2025-05-06 | PXD045506 | Pride

Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response.

Project description:Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.

| S-EPMC11404065 | biostudies-literature

PD-L1 blockade immunotherapy rewires cancer-induced emergency myelopoiesis

Project description:Introduction Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Methods In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow HSPCs. We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality. Results Herein, we reveal that aPD-L1 in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (ÃŽÂ’ÃŽÂœ), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice. Discussion: Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis.

| EGAS00001007873 | EGA

DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion [CRISPR screen]

Project description:RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. We performed targeted RBP CRISPR/Cas9 screening and identified density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibited reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppressed tumor growth and enhanced the tumor-killing activity of CD8+ T cells. Mechanistically, DENR antagonized the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (JAK2); thus, DENR deficiency impaired JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discovered that the RBP DENR is a novel regulator in PD-L1 expression and highlighted the potential of DENR as a therapeutic target for immunotherapy.

2022-02-28 | GSE184048 | GEO

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