Supplementary Data from Local Targeting of NAD<sup>+</sup> Salvage Pathway Alters the Immune Tumor Microenvironment and Enhances Checkpoint Immunotherapy in Glioblastoma
Ming LiAmeya R. KirtaneJuri KiyokawaHiroaki NagashimaAaron LopesZain A. TirmiziChristine K. LeeGiovanni TraversoDaniel P. CahillHiroaki Wakimoto
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<p>Supplemental figures 1-10. Supplementary Figure S1. Cell viability assay with NAMPT inhibitors. Supplementary Figure S2. NAMPT inhibitor induces PD-L1 upregulation on alive cells. Supplementary Figure S3. NAMPT inhibitor induces PD-L1 upregulation. Supplementary Figure S4. Tumor PD-L1 upregulation after injection of coumarin6GMX1778 co-loaded microparticles. Supplementary Figure S5. NAMPT inhibitor-induced autophagy underlies an increase in PD-L1 mRNA and protein levels. Supplementary Figure S6. Impact of local treatment with GMX1778 microparticles on cells labeled with Arg1 and CD68 in murine glioblastoma. Supplementary Figure S7. NAMPT inhibitor decreases glioblastoma-associated macrophages. Supplementary Figure S8. PD-L1 immunohistochemistry (brown) of GL261 glioblastoma after treatment with blank micro-particles (MP), blank MP and anti-PD-1, GMX1778 MP, and combination of GMX1778 MP and anti-PD-1. Supplementary Figure S9. Immunoflurescence of GL261 glioblastoma after treatment with blank micro-particles, anti-PD-1, GMX1778 micro-particles, and combination. Supplementary Figure S10. GranzymeB immunohistochemistry (brown) of GL261 glioblastoma after treatment with blank micro-particles (MP), blank MP and anti-PD-1, GMX1778 MP, and combination of GMX1778 MP and anti-PD-1.</p>Keywords:
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Cancer Immunotherapy
Immune checkpoint
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Tumor progression
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Abstract Objective Immunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway has been observed to be efficient in several solid tumors. We aim to investigate the prognostic significance of PD-1/PD-L1 expression profile in intrahepatic cholangiocarcinoma (ICC). Materials and methods We investigated the expression of PD-1, PD-L1, CD8 + T cells, and CD68 + macrophages in paired tumor and adjacent normal tissues from 322 ICC patients using tyramide signal amplification (TSA)-based multiplexed immunohistochemistry. Results We found that high proportion of tumor-infiltrating CD8 + PD-1 High within CD8 + PD-1 + T cells significantly correlated with advanced TNM stage ( P = 0.035). ICC patients with high proportion of CD8 + PD-1 High in CD8 + PD-1 + had worse postoperative survival than low proportion patients ( P = 0.0037), which was an independently prognostic factor for OS ( P = 0.025,). The density of CD68 + PD-L1 + significantly and positively correlated with the density of CD8 + PD-1 High ( P < 0.0001, r = 0.5927). The proportion of CD68 + PD-L1 + within CD68 + ICC was the risk factor for OS and TTR but not an independently factor for prognosis. The CD68 + PD-L1 + macrophages and CD8 + PD-1 High T cells may cooperatively play a role in inhibiting anti-tumor immunity. Conclusion CD68 + PD-L1 + macrophages and CD8 + PD-1 High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.
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Surgical oncology
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Molecular profiles of different PD-L1 expression in patients with esophageal squamous cell carcinoma
Background PD-1/PD-L1 inhibitors are approved treatments for patients with esophageal squamous cell carcinoma (ESCC). The present investigation aspired to explore the interrelation between molecular phenotype and PD-L1 expression in ESCC.
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Te aim of the study was to evaluate the temporal dynamics of brain CD68+ and stabilin-1+ macrophage infltration in patients with fatal myocardial infarction (MI) type 1. Materials and Methods. Te study included 31 patients with fatal MI type I. Te control group comprised 10 patients of 18–40 age group who died from injuries incompatible with life. Patients with MI were divided into two groups. Group 1 comprised patients who died during the frst 72 hours of MI, group 2 comprised patients who died on days 4‒28. Macrophage infltration in the brain was assessed by immunohistochemical analysis. We used CD68 as a marker for the cells of the macrophage lineage and stabilin-1 as an M2-like macrophage biomarker. Results. In group 1 the number of brain CD68+ macrophages was signifcantly higher than in the control group. In group 2 the intensity of brain CD68+ cells infltration was lower than in group 1 and higher than in the control group. Tere was a small amount of stabilin-1+ macrophages in the brain of healthy people, as well as of patients who died from MI. Tere were no signifcant differences in the number of stabilin-1+ cells between group 1 and group 2. Correlation analysis revealed the presence of positive correlation between the number of CD68 + macrophages in the infarct, peri-infarct, and non-infarct areas of the myocardium and the number of CD68+ macrophages in the brain in patients with MI. Tere were not correlations between the number of CD68 + and stabilin-1+ cells and the presence of diabetes mellitus, history of stroke, history of MI, and pre-infarction angina. Conclusion. Te number of brain CD68+ macrophages signifcantly increased during the frst three days of MI. Te number of brain stabilin-1+ macrophages did not increase and did not differ from the control values. We observed a positive correlation between the number of CD68+ macrophages in the brain and myocardium.
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Abstract Background: Glioma is a type of malignant cancer in the central nervous system. New predictive biomarkers have been investigated in recent years, but the clinical prognosis in glioma remains poor. The function of CPLX2 in glioma and the probable molecular mechanism of tumor suppression was the focus of this investigation. Methods: The glioma transcriptome profile is downloaded from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were performed to analyze the expression of CPLX2 in glioma. RT-qPCR was performed to detect the expression of CPLX2 in 68 glioma subjects, these patients who have been followed up. Kaplan-Meier survival analyses were done to evaluate the effect of CPLX2 on the prognosis of glioma patients. The CPLX2 knockdown and overexpressed cell lines were constructed to investigate the effect of CPLX2 on glioma. The cell growth, colony formation, and tumor formation in xenograft were performed. Results: The expression of CPLX2 was downregulated in glioma and negatively correlated to the grade of glioma. The higher expression of CPLX2 predicted a longer survival through the analysis of Kaplan-Meier survival curves. Overexpressed CPLX2 impaired tumorigenesis in glioma progression both in vivo and in vitro . Knocking down of CPLX2 promoted the proliferation of the glioma cells. The analysis of GSEA and co-expression analysis revealed that CPLX2 may affect the malignancy of glioma by regulating hypoxia and inflammation pathway. Conclusions: Our data indicated that CPLX2 functioned as a tumor suppressor and could be used as a potential prognostic marker in glioma.
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Expression (computer science)
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Multiple studies have confirmed that programmed cell death 1/programmed cell death ligand-1 (PD-1/PD-L1) and immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 play pivotal roles in the treatment of numerous tumors. Patients suffering from cancer are provided hope in the form of immunotherapy. In this review, we discuss the finding that high PD-L1 expression is associated with poor clinical outcomes in prostate cancer patients. Some molecules exert their antitumor effects by downregulating PD-L1 expression in prostate cancer. Additionally, we discuss and summarize the important roles played by anti-PD-1/PD-L1 immunotherapy and its combination with other drugs, including chemotherapy and vaccines, in the treatment of prostate cancer.
Cancer Immunotherapy
Immune checkpoint
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Glioma is a tumor of the brain. Although the clinical regimens and surgical techniques for glioma have improved, therapies of advanced glioma remain challenging, carrying dismal overall survival and therapeutic success rates. Evidence has shown that miRNAs played important roles in glioma development. The current study aimed at investigating the function of a novel cancerogenic miRNA, miR-93, in glioma progression by investigating the expression and mechanism of it.qRT-PCR was conducted to assess the miR-93 expression and the mRNA expression of target gene in glioma tissues and cells. The invasion and migration abilities of the glioma cells were determined by transwell assays. Luciferase reporter assay was performed to confirm the target of miR-93.The results indicated that miR-93 expression in glioma tissues and cells was increased significantly than that in normal brain tissues and cells. Furthermore, miR-93 promoted glioma cell migration and invasion. RBL2 was recognized as a direct target of miR-93 in glioma cells, and overexpression of RBL2 could reverse the stimulative effect of miR-93 in glioma cell.The above findings suggested that miR-93 together with RBL2 could be diagnostic targets and novel prognostic markers for glioma.
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