Impact of PD-L1 overexpression on immune checkpoint inhibitor efficacy in triple-negative breast cancer using a 4T1 murine model.
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE292013 | GEO | 2025/03/28
REPOSITORIES: GEO
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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:Although genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent immune signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. Loss of SMARCAL1 enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a valuable target for cancer immunotherapy.
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Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with
advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8
T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.
2023-06-16 | MSV000092193 | 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
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
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 | GSE250637 | GEO
Project description:This is a mathematical model investigating the effects of continuous and intermittent PD-L1 and anti-PD-L1 therapy upon tumor-immune dynamics.
2019-08-27 | MODEL1908270001 | BioModels
Project description:Background: Previous studies have shown that EZH2 regulates tumor PD-L1 expression at the transcriptional level and has an impact on tumor immune environment and prognosis. However, whether EZH2 can regulate PD-L1 expression at the post-translational level remains unclear. Therefore, this study aims to investigate the effects of EZH2 inhibition on PD-L1 expression and protein stability in colorectal cancer cells, uncover its underlying mechanisms, and provide new therapeutic strategies for anti-tumor immune therapy. Methods: Multiple colorectal cancer cell models were used to examine the effects of EZH2 inhibition on PD-L1 expression and protein stability at both the protein and transcriptional levels. Transcriptome analysis was performed to identify differentially expressed genes associated with EZH2 inhibition and potential effectors involved in EZH2-mediated regulation of PD-L1 protein stability. Validation of candidate genes was conducted through public database analysis and knockdown or overexpression models. Finally, the combined effects of EZH2 inhibitors and anti-PD-1 immune therapy were evaluated using a mouse xenograft model. Results: We observed that inhibition of EZH2 function upregulated PD-L1 expression and enhanced its protein stability in colorectal cancer cells. Transcriptome analysis revealed that ubiquitin-specific protease 22 (USP22) played a crucial role in mediating EZH2-regulated PD-L1 protein stability. EZH2 affected USP22 expression through its classical epigenetic regulatory function, thereby modulating PD-L1 expression stability and influencing the tumor immune microenvironment. Combination treatment with EZH2 inhibitors and anti-PD-1 immune therapy improved the tumor microenvironment, promoted immune cell infiltration, and exerted synergistic anti-cancer effects. Conclusion: This study elucidated the mechanisms by EZH2 regulate PD-L1 expression and stability, providing new insights into therapeutic strategies for colorectal cancer. The combination of EZH2 inhibitors and anti-PD-1 immune therapy can synergistically enhance anti-tumor effects. These findings offer a potential therapeutic approach to improve the effectiveness of EZH2 inhibitors in cancer treatment and contribute to a better understanding of the role of EZH2 in tumor immune regulation.
2024-07-01 | GSE243955 | GEO
Project description:Immune checkpoint blockade (ICB), particularly programmed death 1 (PD-1) and its ligand (PD-L1), has shown considerable clinical benefits in patients with various cancers. Many studies show that PD-L1 expression may be biomarkers to help select responders for anti-PD-1 treatment. Therefore, it is necessary to elucidate the molecular mechanisms that control PD-L1 expression. As a potential chemosensitizer and anticancer drug, copper combined with disulfiram (DSF) kills tumor cells by regulating multiple signaling pathways and transcription factors in vitro and in vivo. Here, we showed that DSF increased PD-L1 expression in triple negative breast cancer (TNBC) cells. Through TCGA data analysis, we found that DNMT1 and IRF7 were highly expressed and the hypermethylation states in the IRF7 gene body promoter region in TNBC vs normal breast tissue (NBT). Then, we demonstrated that DSF affected PD-L1 expression via DNMT1-mediated IRF7 hypomethylation in two TNBC cell lines. In vivo experiments, DSF significantly enhanced the response to PD-1 antibody (Ab) in the triple-negative 4T1 BC mouse model. By analyzing the results of the tumor tissue sequencing, the DSF joint anti-PD-1 Ab could be a significant activation of anti-tumor immunity. And the inactive state of immune associated pathways was found to be reversed, such as Th1 and Th2 cell differentiation, antigen processing and presentation, natural killer cell-mediated cytotoxicity and T cell receptor signal transduction. In conclusion, we found that DSF could up-regulate PD-L1 in TNBC cells and elucidated its mechanism. Our findings revealed that the combination of DSF and anti-PD-1 Ab could activate the tumor immune microenvironment (TIME) to show much better antitumor efficacy than monotherapy.
2021-11-05 | GSE186885 | GEO