Posttranslational Modifications of PD-L1 and Its Prospect Application in Immunotherapy / 中国生物化学与分子生物学报

PD-L1 (programmed cell death 1 ligand 1 ) is an immunosuppressive ligand which mainly expressed on tumor cells, inhibiting the activation of T lymphocytes through binding with PD-1 (programmed cell death protein 1), thus leading to immune escape.PD-1/PD-L1 immune checkpoint blockade therapy, which established based on the above mechanism, gained success in the clinical treatment of solid tumors.Various kinds of PD-L1 posttranslational modifications were identified following the in-depth studies of PD-L1, including glycosylation, phosphorylation, ubiquitination, palmitoylation, et al.Meanwhile, multiple studies indicated that posttranslational modifications governs PD-LI-mediated immune escape through regulating the protein stability and physiological functions of PD-L1, which makes posttranslational modifications of PD-L1 turns into a new "entry" point of PD-L1 studies.Drugs targeting posttranslational modifications of PD-L1 exhibited favorable applicational prospects in immunotherapy at the same time.Regulating PD-L1-mediated immune escape through intervening PD-L1 posttranslational modifications becomes a new strategy for improving the efficacy of immunotherapy.In this review, we summarized the posttranslational modifications of PD-L1 and its applicational prospects in immunotherapy, hoping to provide theoretical supports for future studies focused on PD-L1.

Elevated plasma phage load as a marker for intestinal permeability in leukemic patients.

Microbial translocation (MT) and altered gut microbiota have been described in acute leukemic patients and contribute to immune activation and inflammation. However, phage translocation has not been investigated in leukemia patients yet. We recruited 44 leukemic patients and 52 healthy adults and quantified the levels of 3 phages in peripheral blood, which were the most positive phages screened from fecal samples. The content of 16S rRNA in plasma was detected by qPCR to assess the intestinal mucosa of these patients. Spearman's rank correlation was used to analyze the relationship between phage load and the relevant clinical data. We found the most prevalent phages in fecal samples were λ phage, Wphi phage, and P22 phage, and λ phage had the highest detection rate in plasma (68%). Phage content was affected by chemotherapy and course of disease and correlated with the levels of CRP (r = 0.43, p = 0.003), sCD14 (r = 0.37, p = 0.014), and sCD163 (r = 0.44, p = 0.003). Our data indicate that plasma phage load is a promising marker for gut barrier damage and that gut phage translocation correlates with monocyte/macrophage activation and systemic inflammatory response in leukemic patients.

Regulatory effects of miR-146a/b on the function of endothelial progenitor cells in acute ischemic stroke in mice.

The study aims to explore how microRNA-146a/b (miR-146a/b) regulates the function of endothelial progenitor cells (EPCs) in acute ischemic stroke in mice. Eighty male SPF C57BL/6J mice were evenly divided into the model-6 h, model-12 h, model-24 h (mice suffered from middle cerebral artery occlusion [MCAO] for 6 h, 12 h and model-24 h) and normal groups. EPCs were transfected and assigned into the control, MCAO, MCAO-miR-146a, MCAO-miR-146b and MCAO-miR-146a/b groups. The qRT-PCR was used to detect miR-146a/b expression in EPCs. Expressions of tumor necrosis factor receptor-associated factor 6 (TRAF6) and interleukin-1 receptor-associated kinase 1 (IRAK1) were detected using western blotting. Cell proliferation and migration of EPCs were testified using CCK-8 assay and scratch test, respectively. Angiogenesis ability of EPCs was observed under microscope. MiR-146a and miR-146b expressions were lower in the model groups than the normal group. There were up-regulated TRAF6 and IRAK1 expressions in the model-6 h, model-12 h and model-24 h groups compared with the normal group. And there were down-regulated TRAF6 and IRAK1 expressions in the MCAO-miR-146a, MCAO-miR-146b and MCAO-miR-146a/b groups than in the MCAO group. Compared with the control group, the proliferation, migration and angiogenesis ability of EPCs were significantly lower in the MCAO group, but higher in the MCAO-miR-146a, MCAO-miR-146b and MCAO-miR-146a/b groups. Besides, the miR-146a/b group showed more enhancement than the MCAO-miR-146a and MCAO-miR-146b groups. MiR-146a/b could down-regulate the TRAF6 and IRAK1 expressions and promote proliferation, migration and angiogenesis ability of EPCs, which was important for recovery of patients with hyperacute ischemic stroke.

[Effects of valsartan combined with amlodipine or hydrochlorothiazide regimen on blood pressure variation in elderly hypertensive patients].

OBJECTIVE: To compare the effects of valsartan combined with amlodipine or hydrochlorothiazide regimen on blood pressure variation and plasma nitric oxide (NO) and endothelin (ET) in elderly hypertensive patients. METHODS: A total of 61 elderly patients with grade 2 or 3 hypertension were randomized into valsartan + amlodipine (the amlodipine group, n = 31) or valsartan + hydrochlorothiazide (the hydrochlorothiazide group, n = 30) group. Blood lipids, fasting plasma glucose and uric acid were determined before the treatment. 24-hour dynamic blood pressure, NO and ET were monitored at baseline, 8 and 16 weeks after treatment. RESULTS: 24 hours blood pressure and daytime blood pressure were similar between two groups at all 3 time points. At 16 weeks, morning systolic blood pressure surge was significantly lower in amlodipine group than in hydrochlorothiazide group [(22.6 ± 8.8) mm Hg (1 mm Hg = 0.133 kPa) vs. (26.3 ± 13.7) mm Hg, P < 0.05]. 24 hours systolic blood pressure variability (SBPV) decreased progressively in both groups [the amlodipine group: (12.5 ± 2.8) mm Hg vs. (10.2 ± 2.2) mm Hg vs. (8.8 ± 1.6) mm Hg, P < 0.01; the hydrochlorothiazide group: (12.5 ± 2.5) mm Hg vs. (10.7 ± 2.2) mm Hg vs. (9.6 ± 2.0) mm Hg, P < 0.01]. Daytime SBPV also decreased progressively in both groups [the amlodipine group: (12.2 ± 3.0) mm Hg vs. (10.1 ± 2.3) mm Hg vs. (8.4 ± 1.9) mm Hg, P < 0.01; the hydrochlorothiazide group: (11.8 ± 2.7) mm Hg vs. (10.4 ± 1.9) mm Hg vs. (9.6 ± 2.2) mm Hg, P < 0.01]. 24 hours diastolic blood pressure variability (DBPV) was significantly reduced post therapy in the amlodipine group [(15.5 ± 3.4) mm Hg vs. (13.0 ± 3.5) mm Hg vs. (12.3 ± 2.5), P < 0.01] but not in the hydrochlorothiazide group. NO increased progressively [(27.3 ± 13.6) µmol/L vs. (47.2 ± 16.3) µmol/L vs. (69.5 ± 18.9) µmol/L in the amlodipine group, P < 0.01; (33.5 ± 13.9) µmol/L vs. (49.7 ± 21.9) µmol/L vs. (66.7 ± 24.7) µmol/L in the hydrochlorothiazide group, P < 0.01] and ET decreased progressively [(45.3 ± 8.0) ng/L vs. (37.4 ± 3.9) ng/L vs. (34.2 ± 4.4) ng/L in the amlodipine group, P < 0.01; (46.6 ± 10.4) ng/L vs. (37.0 ± 5.4) ng/L vs. (36.1 ± 8.2) ng/L in the hydrochlorothiazide group, P < 0.01] in both groups. CONCLUSION: Valsartan in combination with amlodipine or hydrochlorothiazide can both effectively lower BPV in elderly hypertensive patients and improve the vascular endothelial function and the former regimen is more suitable for elderly hypertensive patients.