Activation and acetylation of tumor-intrinsic PD-L1 via HBXIP accelerates breast cancer growth
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ABSTRACT:
PROVIDER: PRJNA666208 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12735025_1.fastq.gz | Fastqsanger.gz | |||
| SRR12735025_2.fastq.gz | Fastqsanger.gz | |||
| SRR12735026_1.fastq.gz | Fastqsanger.gz | |||
| SRR12735026_2.fastq.gz | Fastqsanger.gz | |||
| SRR12735027_1.fastq.gz | Fastqsanger.gz |
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Project description:Programmed death ligand-1 (PD-L1) is a well-known transmembrane protein, which antibodies present effective clinical therapy in multiple human cancers. However, the function of tumor cell-intrinsic PD-L1 and its related mechanism in breast cancer remains incompletely studied. Programmed death ligand 1 (PD-L1) on the membrane of tumor cells strengthens tumor immune escape. Tumor cell-intrinsic PD-L1 is also involved in tumorigenesis and development, but the mechanism in regulating PD-L1 expression remains incompletely studied. Here, we report a novel mechanism for PD-L1 that can be induced by hepatitis B X-interacting protein (HBXIP), an oncogenic transcriptional coactivator, promoting breast cancer growth. Overexpression of PD-L1 increases breast cancer proliferation in vitro and in vivo. Transcriptomic analysis also reveals that PD-L1 plays a critical role in cancer development. Furthermore, we find that the expression of PD-L1 is positively associated with HBXIP in breast cancer clinical tissues as well as in cell lines, PD-L1 and HBXIP expression have higher levels in tumor. Mechanistically, HBXIP predominantly stimulates the promoter activity of PD-L1 through coactivating transcription factor ETS2. Especially, HBXIP induced PD-L1 acetylation with the acetyltransferase p300 at lysine 270 (K270), enhancing PD-L1 protein stability. Functionally, depletion of HBXIP markedly attenuates PD-L1-induced breast tumor growth in vitro and in vivo. Moreover, aspirin decreased breast cancer growth via targeting PD-L1 and HBXIP. Taken together, our results extend a new mechanism of PD-L1 functions, expound non-immune effects of PD-L1 and imply broader uses for PD-L1 as a target in breast cancer therapy.
2022-02-02 | GSE158696 | GEO
Project description:Detection of PD-L1 acetylation following in vitro acetylation assay
2021-02-25 | PXD017707 | JPOST Repository
Project description:Although membrane-anchored Pd-l1 has been well-studied for its engagement with PD-1 on T cells to evade anti-tumor immunity, whether Pd-l1 regulate oncogenic signaling pathways in tumor cells remains elusive. In this experiment, to further dissect roles of the K262 residue acetylation for Pd-l1 nuclear function, we profiled RNA expression of WT or K262Q mutant mouse Pd-l1 re-expressed in CT26 KO Pd-l1 cells. Methods: Total RNA fromCT26/Vector, CT26/WT or CT26 Pd-l1 KO cells was purified using Qiagen RNeasy mini kit (Qiagen) according to the manufacturer’s instructions. Library preparation and sequenceing analysis were performed by BGI-Hong Kong Co. Ltd. Conclusions: Our study indicates that Pd-l1 acetylation modification may affect its function in nuclear.
2020-06-07 | GSE146557 | GEO
Project description:MAPK inhibitor (MAPKi) therapy in melanoma leads to accumulation of tumor-surface PD-L1/2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and down-regulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby modulating activation of co-cultured T cells. During MAPKi therapy in vivo, tumor cell-intrinsic ITCH knockdown in murine melanoma induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8+ T cells, and accelerated acquired resistance only in immune-proficient mice. Conversely, tumor cell-intrinsic ITCH over-expression reduced MAPKi-elicited PD-L1 accumulation, augmented cytolytic CD8+ T-cell infiltration, and suppressed acquired resistance in BrafMUT, NrasMUT, and Nf1MUT murine melanoma and KrasMUT pancreatic cancer models. CD8+ T-cell depletion and tumor cell-intrinsic PD-L1 over-expression nullified the ability of ITCH over-expression to suppress MAPKi-resistance, supporting in vivo the ITCH–PD-L1–T-cell regulatory axis demonstrated in human cancer cell lines. Moreover, we identified a small-molecular ITCH activator which suppressed acquired MAPKi-resistance in vivo. Thus, MAPKi-elicited tumor-surface PD-L1 accelerates acquired-resistance, and degrading PD-L1 by activating ITCH may be a combinatorial approach to promote antitumor T-cell immunity and durable responses.
2022-05-31 | GSE199733 | GEO
Project description:Despite the remarkable success of programmed death 1/PD-L1 inhibition in tumor therapy, only a minority of patients benefits from it. Previous studies suggest the anti-PD-1 treatment failure may attribute to the intrinsic functions of PD-L1 in cancer cells. Here, we established a genome-wide CRISPR synthetic lethality screen to systematic explore the PD-L1 intrinsic function in head and neck squamous cell carcinoma (HNSCC) cells. Ferroptosis related genes were identified to be essential for PD-L1 deficient cell viability. Genetic and pharmacological induction of ferroptosis accelerated cell death in PD-L1 knockout cells. PD-L1 knockout cells were also highly susceptible to immunogenic ferroptosis in vitro and in vivo. Mechanistically, nuclear PD-L1 transcriptionally activated SOD2 expression to maintain redox homeostasis. Importantly, the lower ROS and ferroptosis were observed in HNSCC patients with the higher expression of PD-L1. In summary, our study illustrates that PD-L1 confers ferroptosis resistance by activating SOD2-meidated redox homeostasis in HNSCC cells, indicating an enhanced therapeutic effect can be achieved by targeting the intrinsic PD-L1 function during immunotherapy.
2024-07-08 | GSE268534 | GEO
Project description:Despite the remarkable success of programmed death 1/PD-L1 inhibition in tumor therapy, only a minority of patients benefits from it. Previous studies suggest the anti-PD-1 treatment failure may attribute to the intrinsic functions of PD-L1 in cancer cells. Here, we established a genome-wide CRISPR synthetic lethality screen to systematic explore the PD-L1 intrinsic function in head and neck squamous cell carcinoma (HNSCC) cells. Ferroptosis related genes were identified to be essential for PD-L1 deficient cell viability. Genetic and pharmacological induction of ferroptosis accelerated cell death in PD-L1 knockout cells. PD-L1 knockout cells were also highly susceptible to immunogenic ferroptosis in vitro and in vivo. Mechanistically, nuclear PD-L1 transcriptionally activated SOD2 expression to maintain redox homeostasis. Importantly, the lower ROS and ferroptosis were observed in HNSCC patients with the higher expression of PD-L1. In summary, our study illustrates that PD-L1 confers ferroptosis resistance by activating SOD2-meidated redox homeostasis in HNSCC cells, indicating an enhanced therapeutic effect can be achieved by targeting the intrinsic PD-L1 function during immunotherapy.
2024-07-08 | GSE268533 | GEO
Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress
Project description:Cancer immunotherapy has focused on inhibitors of checkpoint proteins, such as Programmed Death Ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, we assumed that intrinsic and microenvironmental factors are involved. Among all non-immunological signaling pathways we surveyed in patients’ datasets, EGFR signaling best associated with high PD-L1. Correspondingly, active EGFRs stabilized PD-L1’s transcripts and depleting PD-L1 severely inhibited EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve recruitment of phospholipase C-g1 (PLC-g1) to a cytoplasmic motif of PD-L1, which enhances PLC-g1 activation by EGFR. Once stimulated, PLC-g1 activates calcium flux, RHO GTPases and protein kinase C, which promotes an aggressive phenotype. Furthermore, anti-PD-L1 antibodies can inhibit these intrinsic functions of PD-L1. Our results portray PD-L1 as a molecular amplifier of EGFR signaling and lay the foundation for understanding resistance of EGFR+ tumors to immunotherapy.
2021-04-08 | GSE171650 | GEO
Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.
2022-03-31 | MSV000089180 | MassIVE
Project description:Programmed cell death 1 ligand 1 (PD-L1) is known to suppress immune system and to be an unfavorable prognostic factor in ovarian cancer. The purpose of this study was to elucidate the function of PD-L1 in peritoneal dissemination. Tumor cell lysis by CTLs was attenuated when PD-L1 on tumor cells was overexpressed and promoted when it was silenced. PD-L1 overexpression also inhibited gathering and degranulation of CTLs. Gene expression profile of mouse CTLs caused by PD-L1-overexpressing ovarian cancer was related to human CTLs exhaustion. In mouse ovarian cancer dissemination models, depleting PD-L1 expression on tumor cells resulted in inhibited tumor growth in the peritoneal cavity and prolonged survival. Restoring immune function by inhibiting immune-suppressive factors such as PD-L1 may be a promising therapeutic strategy for peritoneal dissemination. Genome-wide transcriptional changes in OT-1 mouse CD8+ T cells that were co-incubated with OVA peptide-loaded ID8 mouse ovarian cancer cell lines. CTLs from 4 mice were devided into 2 groups, and co-incubated with PD-L1-overexpressed ID8 or PD-L1-depleted ID8.
2012-07-09 | E-GEOD-39205 | biostudies-arrayexpress