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Lipidoid Nanoparticles Containing PD-L1 siRNA Delivered In Vivo Enter Kupffer Cells and Enhance NK and CD8(+) T Cell-mediated Hepatic Antiviral Immunity.

ABSTRACT: Effective clinical application of antiviral immunotherapies necessitates enhancing the functional state of natural killer (NK) and CD8(+) T cells. An important mechanism for the establishment of viral persistence in the liver is the activation of the PD-1/PD-L1 inhibitory pathway. To examine the role of hepatic myeloid PD-L1 expression during viral infection, we determined the magnitude and quality of antiviral immune responses by administering PD-L1 short-interfering RNA (siRNA) encapsulated in lipidoid nanoparticles (LNP) in mice. Our studies indicate that Kupffer cells (KC) preferentially engulfed PD-L1 LNP within a short period of time and silenced Pdl1 during adenovirus and MCMV infection leading to enhanced NK and CD8(+) T cell intrahepatic accumulation, effector function (interferon (IFN)-γ and granzyme B (GrB) production), CD8(+) T cell-mediated viral clearance, and memory. Our results demonstrate that PD-L1 knockdown on KCs is central in determining the outcome of liver viral infections, and they represent a new class of gene therapy.Molecular Therapy - Nucleic Acids (2013) 2, e72; doi:10.1038/mtna.2012.63; published online 19 February 2013.

SUBMITTER: Dolina JS

PROVIDER: S-EPMC3586800 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other

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Lipidoid Nanoparticles Containing PD-L1 siRNA Delivered In Vivo Enter Kupffer Cells and Enhance NK and CD8(+) T Cell-mediated Hepatic Antiviral Immunity.

Dolina Joseph S JS Sung Sun-Sang J SS Novobrantseva Tatiana I TI Nguyen Tuyen M TM Hahn Young S YS

Molecular therapy. Nucleic acids 20130219

Effective clinical application of antiviral immunotherapies necessitates enhancing the functional state of natural killer (NK) and CD8(+) T cells. An important mechanism for the establishment of viral persistence in the liver is the activation of the PD-1/PD-L1 inhibitory pathway. To examine the role of hepatic myeloid PD-L1 expression during viral infection, we determined the magnitude and quality of antiviral immune responses by administering PD-L1 short-interfering RNA (siRNA) encapsulated in ...[more]

PMID: 23423360

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Project description:BACKGROUND:Brain metastases (Bmets) are frequent; however, limited data exist on the efficacy of immunotherapy in these lesions. The aims of the study were to analyze the immunohistochemical expressions of programmed death ligand 1 (PD-L1) and CD8 in Bmets and to compare them with their expressions in paired primary tumors, as well as correlate the results with clinicopathological features. METHODS:This is a retrospective study of 233 patients with Bmets and 111 paired primaries. Clinical, histological, and molecular data were recorded and compared with the immunohistochemical results of PD-L1 and CD8 expressions. The statistical analysis included ?2 test, Cramer's V test, factorial analyses of variance, simple regression analysis, and Kaplan-Meier analysis with log-rank product limit estimation. RESULTS:PD-L1 expression was found in 23.6% of Bmets and in 29.0% of primary tumors with concordant expression between them in 75.5% of cases. Bmets PD-L1 expression was associated with primary tumor PD-L1 expression and the primary tumor type. Significant CD8 peritumoral expression was found in 68.6% of Bmets and in 87.7% of primary tumors. CD8 expression was concordant between primary and metastatic tumors in 73.3% of cases. Bmets CD8 expression was associated with primary tumor CD8 expression and primary tumor type. PD-L1 expression was associated with CD8 expression in both primary and metastatic tumors. The concordance between primary and metastatic tumor PD-L1 expression was independent of all factors studied. The concordance between primary and metastatic CD8 expressions was marginally associated to the time of Bmets development. No prognostic role for PD-L1 and CD8 expression in Bmets was found. CONCLUSION:PD-L1 and CD8 Bmets expressions are associated with the primary tumor type and its PD-L1 and CD8 expressions. No factor predicts the discordance for PD-L1 expression, while time to Bmets development is associated with CD8 expression discordance.

Project description:Exosomal PD-L1 (exoPD-L1) is reported to be associated with immunosuppression in various cancers. However, its clinical value in extranodal NK/T cell lymphoma (ENKTL) has not been defined yet. We retrospectively evaluated the prognostic value of pretreatment circulating soluble PD-L1 (sPD-L1) and exosomal PD-L1 (exoPD-L1) in ENKTL patients treated with VIPD-containing chemotherapy. A total of 107 ENKTL patients, including 101 early stage and 6 advanced stage patients were enrolled in our study. ExoPD-L1 and sPD-L1 in the blood were measured by single molecule array (Simoa) and enzyme-linked immunosorbent assay (ELISA), respectively. Compared with the healthy individuals (n=16), the patients with ENKTL (n=107) exhibited significantly elevated exoPD-L1 and sPD-L1 levels in the blood. High pretreatment plasma exoPD-L1 concentration was associated with higher SUVmax level and recurrence rate. Similarly, high sPD-L1 group was also associated with some adverse clinical parameters, including advanced stage, elevated LDH levels, B symptoms, high IPI score and PINK score. The 5-year progression-free survival (PFS) rate and overall survival (OS) rates were 65.2% and 85.7% for the whole cohort, respectively. Patients with a low pretreatment exoPD-L1 level (simoa signal < 1.2) had 5-year OS and PFS rates of 88.1% and 86.1%, respectively, compared with 56.0%. (P=0.012) and 35.7% (P=0.007) in patients with high exoPD-L1 level (simoa signal > 1.2). The 5-year OS and PFS rates for patients with low sPD-L1 group (< 219 pg/mL) was significantly higher than high sPD-L1 group (≥ 219 pg/mL) (OS, 91.3% vs. 55.5%, P < 0.001; PFS, 68.9% vs. 34.6%, P=0.003). However, no correlation was found between circulating exoPD-L1 and sPD-L1 levels. This is the first study to measure plasma exoPD-L1 level on the Quanterix Simoa platform. Our results proved that circulating exoPD-L1 and sPD-L1 levels were significantly elevated in ENKTL and might be potential biomarkers for predicting the survival outcomes of ENKTL patients.

Dataset Information

Lipidoid Nanoparticles Containing PD-L1 siRNA Delivered In Vivo Enter Kupffer Cells and Enhance NK and CD8(+) T Cell-mediated Hepatic Antiviral Immunity.

Publications

Lipidoid Nanoparticles Containing PD-L1 siRNA Delivered In Vivo Enter Kupffer Cells and Enhance NK and CD8(+) T Cell-mediated Hepatic Antiviral Immunity.

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