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Regulation of programmed cell death ligand 1 expression by atypical protein kinase C lambda/iota in cutaneous angiosarcoma.

ABSTRACT: The expression of immune checkpoint proteins such as programmed cell death protein 1 (PD-1) and its ligand (PD-L1) has been shown to correlate with patient prognosis in many malignant cancers. The expression of PD-L1 is controlled by c-Myc; however, further upstream regulation of PD-L1 expression is largely unknown. We have previously shown that atypical protein kinase C lambda/iota (aPKCλ) phosphorylates the Forkhead box protein O1 (FoxO1) transcription factor at Ser218 to suppress its DNA-binding ability, thereby regulating c-Myc expression and controlling physiologic and pathologic endothelial proliferation. The presence of phosphorylation of FoxO1 at Ser218 (pSer218 FoxO1) in cutaneous angiosarcoma (CAS) strongly correlates with poor patient prognosis. Here, we reported that patients with PD-L1⁺ cells in CAS lesions showed significantly worse prognosis compared to those that were PD-L1^- . Expression of PD-L1 correlated with that of aPKCλ or the presence of pSer218FoxO1. Moreover, suppression of aPKCλ expression or inhibition of its activity in HUVECs or AS-M, an established human angiosarcoma cell line, resulted in decreased PD-L1 expression. Our results suggest that combined treatment with immune checkpoint inhibitors and aPKCλ inhibitors could be a novel treatment strategy for CAS patients.

SUBMITTER: Kawamura A

PROVIDER: S-EPMC6500975 | biostudies-literature |

REPOSITORIES: biostudies-literature

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GLI activation by atypical protein kinase C ι/λ regulates the growth of basal cell carcinomas.

Project description:Growth of basal cell carcinomas (BCCs) requires high levels of hedgehog (HH) signalling through the transcription factor GLI. Although inhibitors of membrane protein smoothened (SMO) effectively suppress HH signalling, early tumour resistance illustrates the need for additional downstream targets for therapy. Here we identify atypical protein kinase C ι/λ (aPKC-ι/λ) as a novel GLI regulator in mammals. aPKC-ι/λ and its polarity signalling partners co-localize at the centrosome and form a complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates HH signalling. Genetic or pharmacological loss of aPKC-ι/λ function blocks HH signalling and proliferation of BCC cells. Prkci is a HH target gene that forms a positive feedback loop with GLI and exists at increased levels in BCCs. Genome-wide transcriptional profiling shows that aPKC-ι/λ and SMO control the expression of similar genes in tumour cells. aPKC-ι/λ functions downstream of SMO to phosphorylate and activate GLI1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC-ι/λ is upregulated in SMO-inhibitor-resistant tumours and targeting aPKC-ι/λ suppresses signalling and growth of resistant BCC cell lines. These results demonstrate that aPKC-ι/λ is critical for HH-dependent processes and implicates aPKC-ι/λ as a new, tumour-selective therapeutic target for the treatment of SMO-inhibitor-resistant cancers.

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Def-6, a novel regulator of small GTPases in podocytes, acts downstream of atypical protein kinase C (aPKC) λ/ι.

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| S-EPMC5707189 | biostudies-literature

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| S-EPMC1222137 | biostudies-other

Programmed death-ligand 1 expression in swine chronic infections and enhancement of interleukin-2 production via programmed death-1/programmed death-ligand 1 blockade.

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Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4<sup>+</sup> T Effector and Regulatory T Cells in Cutaneous Leishmaniasis.

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| S-EPMC7642203 | biostudies-literature

Inhibition of Programmed Death Receptor-1/Programmed Death Ligand-1 Interactions by Ginsenoside Metabolites.

Project description:Evidence suggests that programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) targeted inhibitors act as an immune checkpoint blockade, indicating that these compounds may be useful in cancer immunotherapy by inhibiting the immune response between T-cells and tumors. Previous studies have shown that ginsenosides can regulate the expression of PD-1 and PD-L1 in target diseases; however, it remains unknown whether ginsenosides act as a blockade of PD-1/PD-L1 interactions. In this study, we used competitive ELISA to investigate 12 ginsenosides for their ability to block PD-1/PD-L1 interactions. In addition, we performed a protein-ligand docking simulation and examined the hydrophobic interactions and hydrogen bonds formed at the interfaces between the ginsenosides and PD-L1/PD-1. Eight out of the 12 ginsenosides studied showed inhibition of PD-1/PD-L1 interactions at 35% at the maximum concentration (1 μM). Among them, Rg3 and Compound K (C-K) demonstrated the highest inhibitory effects. Rg3 and C-K were further identified for their interaction efficacy with PD-1/PD-L1, which supported our results demonstrating the blocking activity of these compounds against PD-1/PD-L1 binding interactions. Collectively, our findings suggest that some ginsenosides, including Rg3 and C-K, inhibit PD-1/PD-L1 binding interactions. Therefore, these compounds may prove useful as part of an overall immuno-oncological strategy.

| S-EPMC7249111 | biostudies-literature

Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality.

Project description:Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.

| S-EPMC3811178 | biostudies-literature

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