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ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation.

ABSTRACT: Cancer expression of PD-L1 suppresses anti-tumor immunity. PD-L1 has emerged as a remarkable therapeutic target. However, the regulation of PD-L1 degradation is not understood. Here, we identify several compounds as inducers of PD-L1 degradation using a high-throughput drug screen. We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283. We identify ARIH1 as the E3 ubiquitin ligase responsible for targeting PD-L1 to degradation. Overexpression of ARIH1 suppresses tumor growth and promotes cytotoxic T cell activation in wild-type, but not in immunocompromised mice, highlighting the role of ARIH1 in anti-tumor immunity. Moreover, combining EGFR inhibitor ES-072 with anti-CTLA4 immunotherapy results in an additive effect on both tumor growth and cytotoxic T cell activation. Our results delineate a mechanism of PD-L1 degradation and cancer escape from immunity via EGFR-GSK3α-ARIH1 signaling and suggest GSK3α and ARIH1 might be potential drug targets to boost anti-tumor immunity and enhance immunotherapies.

SUBMITTER: Wu Y

PROVIDER: S-EPMC8058344 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ARIH1 Signaling Promotes Anti-tumor Immunity by Targeting PD-L1 for Proteasomal Degradation

Project description:We find EGFR inhibitors promote PD-L1 ubiquitination and proteasomal degradation following GSK3α-mediated phosphorylation of Ser279/Ser283.

2021-03-01 | PXD024452 |

BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression.

Project description:Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression.

| S-EPMC5177024 | biostudies-literature

KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC.

Project description:Immunotherapy has become a prominent first-line cancer treatment strategy. In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy. However, little is known about the regulation mechanism and the function of PD-L1 in lung cancer. In this study, we have discovered that KEAP1 serves as an E3 ligase to promote PD-L1 ubiquitination and degradation. We found that overexpression of KEAP1 suppressed tumor growth and promoted cytotoxic T-cell activation in vivo. These results indicate the important role of KEAP1 in anti-cancer immunity. Moreover, the combination of elevated KEAP1 expression with anti-PD-L1 immunotherapy resulted in a synergistic effect on both tumor growth and cytotoxic T-cell activation. Additionally, we found that the expressions of KEAP1 and PD-L1 were associated with NSCLC prognosis. In summary, our findings shed light on the mechanism of PD-L1 degradation and how NSCLC immune escape through KEAP1-PD-L1 signaling. Our results also suggest that KEAP1 agonist might be a potential clinical drug to boost anti-tumor immunity and improve immunotherapies in NSCLC.

| S-EPMC10899596 | biostudies-literature

Benzosceptrin C induces lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting DHHC3.

Project description:Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blockade has become a mainstay of cancer immunotherapy. Targeting the PD-1/PD-L1 axis with small molecules is an attractive approach to enhance antitumor immunity. Here, we identified a natural marine product, benzosceptrin C (BC), that enhances the cytotoxicity of T cells to cancer cells by reducing the abundance of PD-L1. Furthermore, BC exerts its antitumor effect in mice bearing MC38 tumors by activating tumor-infiltrating T cell immunity. Mechanistic studies suggest that BC can prevent palmitoylation of PD-L1 by inhibiting DHHC3 enzymatic activity. Subsequently, PD-L1 is transferred from the membrane to the cytoplasm and cannot return to the membrane via recycling endosomes, triggering lysosome-mediated degradation of PD-L1. Moreover, the combination of BC and anti-CTLA4 effectively enhances antitumor T cell immunity. Our findings reveal a previously unrecognized antitumor mechanism of BC and represent an alternative immune checkpoint blockade (ICB) therapeutic strategy to enhance the efficacy of cancer immunotherapy.

| S-EPMC10897506 | biostudies-literature

Suppression of PD-L1 release from small extracellular vesicles promotes systemic anti-tumor immunity by targeting ORAI1 calcium channels.

Project description:Blockade of immune checkpoints as a strategy of cancer cells to overcome the immune response has received ample attention in cancer research recently. In particular, expression of PD-L1 by various cancer cells has become a paradigm in this respect. Delivery of PD-L1 to its site of action occurs either by local diffusion, or else by transport via small extracellular vesicles (sEVs, commonly referred to as exosomes). Many steps of sEVs formation, their packaging with PD-L1 and their release into the extracellular space have been studied in detail. The likely dependence of release on Ca2+ -signaling, however, has received little attention. This is surprising, since the intracellular Ca2+ -concentration is known as a prominent regulator of many secretory processes. Here, we report on the roles of three Ca2+ -dependent proteins in regulating release of PD-L1-containing sEVs, as well as on the growth of tumors in mouse models. We show that sEVs release in cancer cell lines is Ca2+ -dependent and the knockdown of the gene coding the Ca2+ -channel protein ORAI1 reduces Ca2+ -signals and release of sEVs. Consequently, the T cell response is reinvigorated and tumor progression in mouse models is retarded. Furthermore, analysis of protein expression patterns in samples from human cancer tissue shows that the ORAI1 gene is significantly upregulated. Such upregulation is identified as an unfavorable prognostic factor for survival of patients with non-small-cell lung cancer. We show that reduced Ca2+ -signaling after knockdown of ORAI1 gene also compromises the activity of melanophilin and Synaptotagmin-like protein 2, two proteins, which are important for correct localization of secretory organelles within cancer cells and their transport to sites of exocytosis. Thus, the Ca2+ -channel ORAI1 and Ca2+ -dependent proteins of the secretion pathway emerge as important targets for understanding and manipulating immune checkpoint blockade by PD-L1.

| S-EPMC9732629 | biostudies-literature

Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation.

Project description:Immune checkpoint blockade therapies targeting the PD-L1/PD-1 axis have demonstrated clear clinical benefits. Improved understanding of the underlying regulatory mechanisms might contribute new insights into immunotherapy. Here, we identify transmembrane and ubiquitin-like domain-containing protein 1 (TMUB1) as a modulator of PD-L1 post-translational modifications in tumor cells. Mechanistically, TMUB1 competes with HECT, UBA and WWE domain-containing protein 1 (HUWE1), a E3 ubiquitin ligase, to interact with PD-L1 and inhibit its polyubiquitination at K281 in the endoplasmic reticulum. Moreover, TMUB1 enhances PD-L1 N-glycosylation and stability by recruiting STT3A, thereby promoting PD-L1 maturation and tumor immune evasion. TMUB1 protein levels correlate with PD-L1 expression in human tumor tissue, with high expression being associated with poor patient survival rates. A synthetic peptide engineered to compete with TMUB1 significantly promotes antitumor immunity and suppresses tumor growth in mice. These findings identify TMUB1 as a promising immunotherapeutic target.

| S-EPMC9663433 | biostudies-literature

Tubeimoside-1 induces TFEB-dependent lysosomal degradation of PD-L1 and promotes antitumor immunity by targeting mTOR.

Project description:Programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) cascade is an effective therapeutic target for immune checkpoint blockade (ICB) therapy. Targeting PD-L1/PD-1 axis by small-molecule drug is an attractive approach to enhance antitumor immunity. Using flow cytometry-based assay, we identify tubeimoside-1 (TBM-1) as a promising antitumor immune modulator that negatively regulates PD-L1 level. TBM-1 disrupts PD-1/PD-L1 interaction and enhances the cytotoxicity of T cells toward cancer cells through decreasing the abundance of PD-L1. Furthermore, TBM-1 exerts its antitumor effect in mice bearing Lewis lung carcinoma (LLC) and B16 melanoma tumor xenograft via activating tumor-infiltrating T-cell immunity. Mechanistically, TBM-1 triggers PD-L1 lysosomal degradation in a TFEB-dependent, autophagy-independent pathway. TBM-1 selectively binds to the mammalian target of rapamycin (mTOR) kinase and suppresses the activation of mTORC1, leading to the nuclear translocation of TFEB and lysosome biogenesis. Moreover, the combination of TBM-1 and anti-CTLA-4 effectively enhances antitumor T-cell immunity and reduces immunosuppressive infiltration of myeloid-derived suppressor cells (MDSCs) and regulatory T (Treg) cells. Our findings reveal a previously unrecognized antitumor mechanism of TBM-1 and represent an alternative ICB therapeutic strategy to enhance the efficacy of cancer immunotherapy.

| S-EPMC8551420 | biostudies-literature

Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1.

Project description:Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.

| S-EPMC6786495 | biostudies-literature

NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1.

Project description:Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically "hot" pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.

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Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.

Project description:T cell infiltration of solid tumors is associated with favorable patient outcomes, yet the mechanisms underlying variable immune responses between individuals are not well understood. One possible modulator could be the intestinal microbiota. We compared melanoma growth in mice harboring distinct commensal microbiota and observed differences in spontaneous antitumor immunity, which were eliminated upon cohousing or after fecal transfer. Sequencing of the 16S ribosomal RNA identified Bifidobacterium as associated with the antitumor effects. Oral administration of Bifidobacterium alone improved tumor control to the same degree as programmed cell death protein 1 ligand 1 (PD-L1)-specific antibody therapy (checkpoint blockade), and combination treatment nearly abolished tumor outgrowth. Augmented dendritic cell function leading to enhanced CD8(+) T cell priming and accumulation in the tumor microenvironment mediated the effect. Our data suggest that manipulating the microbiota may modulate cancer immunotherapy.

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