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PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients.

ABSTRACT: Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4+ T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in both cohorts and that STAT1-dependent PD-L1 up-regulation-known to inhibit Th17 differentiation in mouse models-was markedly enhanced as well. Overexpression of SOCS3 strongly inhibited phosphorylation of STAT1 and PD-L1 up-regulation, suggesting that diminished SOCS3 expression may lead to the observed effects. Defects in Th17 differentiation could be partially overcome in vitro via PD-L1 inhibition and in a mouse model of STAT3 loss-of-function by crossing them with PD-1 knockout mice. PD-L1 may be a potential therapeutic target in several genetic diseases of immune deficiency affecting cytokine signaling.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC5584116 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients.

Zhang Yuan Y Ma Chi A CA Lawrence Monica G MG Break Timothy J TJ O'Connell Michael P MP Lyons Jonathan J JJ López Diego B DB Barber John S JS Zhao Yongge Y Barber Daniel L DL Freeman Alexandra F AF Holland Steven M SM Lionakis Michail S MS Milner Joshua D JD

The Journal of experimental medicine 20170714 9

Patients with hypomorphic mutations in STAT3 and patients with hypermorphic mutations in STAT1 share several clinical and cellular phenotypes suggesting overlapping pathophysiologic mechanisms. We, therefore, examined cytokine signaling and CD4+ T cell differentiation in these cohorts to characterize common pathways. As expected, differentiation of Th17 cells was impaired in both cohorts. We found that STAT1 was hyperphosphorylated in response to cytokine stimulation in ...[more]

PMID: 28710273

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Project description:Rationale: Abnormal expression of programmed death-1 (PD-1) ligand-1(PD-L1) in cancer cells plays a crucial role in cancer immune evasion and progression. The immune checkpoint molecules PD-1 and PD-L1 have been targeted for cancer treatment with significant benefits for cancer patients. However, the response rate is relatively low in certain types of cancer and the underlying mechanism remains poorly understood. Better understanding of the molecular mechanism of PD-L1 expression regulation in cancer cells is urgently needed to improve the treatment response rate and overall survival of patients. Fructose-1, 6-biphosphatase (FBP1) is a key enzyme in gluconeogenesis and is implicated in human cancer due to its frequent loss in various cancer types. Methods: Expression of FBP1 and PD-L1 was analyzed in various cancer cell lines. Western blot and RT-qPCR were performed to determine whether FBP1 regulates PD-L1 expression. Co-immunoprecipitation and glutathione S-transferase (GST) pulldown assay were employed to define the underlying regulatory mechanisms. Immunohistochemistry was conducted to determine the correlation between FBP1 and PD-L1 expression in a cohort of patients. A cancer syngeneic mouse model was utilized to examine how FBP1 affects tumor immunity. Results: We demonstrated that in a manner independent of its enzymatic activity FBP1 downregulates the expression of PD-L1 in various cell lines of different cancer types including pancreatic and prostate cancer. We further showed that this regulation occurs at the transcriptional level and is mediated by FBP1 inhibition of signal transducer and activator of transcription-3 (STAT3)-dependent PD-L1 transcription. Moreover, FBP1 and PD-L1 protein expression were negatively correlated in pancreatic ductal adenocarcinoma (PDAC) specimens from a cohort of patients. Most importantly, we demonstrated that decreased FBP1 expression promotes tumor growth and resistance to immune checkpoint blockade therapy in mice. Conclusions: Our findings reveal a new tumor suppressor function of FBP1 in inhibiting PD-L1 expression and enhancing cancer immunity. They also suggest that FBP1-deficient human cancers could be therapeutically targeted by PD-1/PD-L1-based immune checkpoint blockade therapy.

Project description:PD-L1 has been characterized as an inhibitory immune checkpoint, leading to the suppression of potential anti-tumor immune activities in many cancer types. In view of the relatively limited efficacy of immune checkpoint blockades against PD-L1 in breast cancer, our recent study addressed the possibility that in addition to its immune-inhibitory functions, PD-L1 promotes the pro-metastatic potential of the cancer cells themselves. Indeed, our published findings demonstrated that PD-L1 promoted pro-metastatic functions of breast cancer cells in a cell-autonomous manner, both in vitro and in vivo. These functions fully depended on the integrity of the S283 intracellular residue of PD-L1. Here, using siRNAs and the S283A-PD-L1 variant, we demonstrate that the cell-autonomous pro-metastatic functions of PD-L1-tumor cell proliferation and invasion, and release of the pro-metastatic chemokine CXCL8-required the activation of STAT3 and STAT1 in luminal A and triple-negative breast cancer cells. The cell-autonomous pro-metastatic functions of PD-L1 were potently impaired upon inhibition of N-linked glycosylation (kifunensine). Site-specific mutants at each of the N-linked glycosylation sites of PD-L1 (N35, N192, N200, and N219) revealed that they were all required for PD-L1-induced pro-metastatic functions to occur; the N219 site was the main regulator of STAT3 and STAT1 activation, with accompanying roles for N192 and N200 (depending on the cell type). Using a T cell-independent mouse system, we found that cells expressing N35A-PD-L1 and N219A-PD-L1 had a significantly lower tumorigenic and metastatic potential than cells expressing WT-PD-L1. TCGA analyses revealed significant associations between reduced survival and high levels of α-mannosidase II (inferring on N-linked glycosylation) in breast cancer patients. These findings suggest that N-linked glycosylation of PD-L1 may be used to screen for patients who are at greater risk of disease progression, and that modalities targeting N-linked glycosylated PD-L1 may lead to the inhibition of its cell-autonomous pro-metastatic functions and to lower tumor progression in breast cancer.

Dataset Information

PD-L1 up-regulation restrains Th17 cell differentiation in STAT3 loss- and STAT1 gain-of-function patients.

Publications

PD-L1 up-regulation restrains Th17 cell differentiation in <i>STAT3</i> loss- and <i>STAT1</i> gain-of-function patients.

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