scholarly journals Maprotiline Prompt the Anti-tumor Effect by Inhibiting the PD-L1 in Mice Burdened Melanoma

2021 ◽  
Author(s):  
Tiesuo Zhao ◽  
Yang Li ◽  
Miaomiao Liu ◽  
Lin Zhou ◽  
Zunge Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Tumor Tissues ◽  
Programmed Cell Death 1 ◽  
Tetracyclic Antidepressant ◽  
And Migration ◽  
Cell Death Protein

Abstract Programmed cell death 1 ligand 1(PD-L1) binds with programmed cell death protein 1 (PD-1) to inhibit the responses of T cells. PD-L1 is significantly upregulated on tumor cells and blocking the PD-L1/PD-1 signal has become an important target of immunotherapy in clinic. At present, some old drugs of non-antitumor have been found that could play the effect of anti-tumor. Maprotiline, as a tetracyclic antidepressant, has been widely used for treating mental depression. Here, we study the anti-tumor effect of maprotiline by strengthening the immune response of mice. In vitro, treatment with maprotiline inhibits the proliferation and migration of B16 cells, increases the cell apoptosis. Importantly, treatment with maprotiline reduces the expression of PD-L1 in tumor tissue, prompts the ratios of CD4+ T cells, CD8+ T cells and NK cells in spleens, increases the infiltration of CD4+ and CD8+ T cells in tumor-tissues. In brief, we determine that maprotiline could prompt the anti-tumor immune response by inhibiting the PD-L1 in mice. This study may find a new inhibitor of PD-L1, which provides a new drug treated tumor in clinical.

scholarly journals PD-L1 Inhibitors: Different Classes, Activities, and Mechanisms of Action

2021 ◽  
Vol 22 (21) ◽  
pp. 11797
Author(s):  
Ewa Surmiak ◽  
Katarzyna Magiera-Mularz ◽  
Bogdan Musielak ◽  
Damian Muszak ◽  
Justyna Kocik-Krol ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint Blockade ◽  
Mechanisms Of Action ◽  
In Vitro Bioactivity ◽  
Drug Candidates ◽  
Programmed Cell Death 1 ◽  
Blocking Activity ◽  
Cell Death Protein

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.

Altered Expression of Immune Checkpoint Molecules Including Programmed Cell Death-1 (PD-1) and Its Ligands PD-L1/PD-L2 in Waldenstrom's Macroglobulinemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1772-1772 ◽  
Author(s):  
Shahrzad Jalali ◽  
Tammy Price-Troska ◽  
Anne J. Novak ◽  
Stephen M Ansell
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Immune Checkpoint Molecules ◽  
Programmed Cell Death 1

Abstract Waldenstrom's Macroglobulinemia (WM) is an indolent B-cell malignancy that is characterized by bone marrow infiltration of lymphoplasmacytic cells and excessive synthesis of IgM. Despite improved treatment strategies and increased understanding of the underlying molecular mechanisms contributing to malignant disease progression, WM remains incurable. While whole exome sequencing analysis has revealed the genomic events associated with malignant B cell transformation in WM, the bone marrow (BM) microenvironment is also emerging as a major player in the pathogenesis of WM. Previously, our lab has reported that an array of cytokines, including IL-21 and IL-6 are increased in the WM BM and such increases are associated with high proliferation rates and IgM secretion by WM cells. In this study, we aimed to identify how immune checkpoint molecules in the BM microenvironment, specifically programmed cell death-1 (PD-1) and its ligands PD-L1 and PD-L2, contribute to malignant cell expansion in WM. Using Real-Time PCR analysis, we show that the expression of PD-1, PD-L1 and PD-L2 are all significantly elevated in the cells of WM BM as compared to their normal BM counterparts. Interestingly, PD-L1 expression is also upregulated in the malignant WM cells. These findings were further confirmed by flow cytometry analysis. Subsequent in vitro analysis showed that PD-L1 and PD-L2 are cleaved from the WM cells and these soluble ligands (sPD-L1 and sPD-L2) are able to bind to the cells in the BM microenvironment, including T-cells. This results in reduced activation and proliferation of T-cells, and is accompanied by a reduction in cyclin A and p-ERK levels. In validation of the in vitro data, we also found sPD-L1 and sPD-L2 in the bone marrow plasma obtained from WM patients. While sPD-L2 was found to be present in both WM and normal BM plasma (though in a reduced level in WM), sPD-L1 was exclusive to the WM samples, implying that the function of these molecules are differentially regulated in WM. Furthermore, overexpression of PD-L1 in a WM cell line, MWCL.1, resulted in an increase in IgM secretion. Interestingly, treatment with IL-21 increased the expression of PD-L1 in WM cells, indicating that elevated IL-21 in WM BM could contribute to increased expression of PD-L1 by malignant WM cells. In summary, our data support a role for PD-1 ligands as immune regulatory molecules in WM. Further studies are ongoing to explore the molecular mechanisms by which PD-1/PD-L1/PD-L2 signaling affects the pathophysiology of WM cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Response to Programmed Cell Death-1 Blockade in a Murine Melanoma Syngeneic Model Requires Costimulation, CD4, and CD8 T Cells

2016 ◽  
Vol 4 (10) ◽  
pp. 845-857 ◽  
Author(s):  
Blanca Homet Moreno ◽  
Jesse M. Zaretsky ◽  
Angel Garcia-Diaz ◽  
Jennifer Tsoi ◽  
Giulia Parisi ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Cd8 T Cells ◽  
Murine Melanoma ◽  
Programmed Cell Death 1 ◽  
Syngeneic Model

Side effects of immune-checkpoint inhibitors: Can multiple side effects be seen in a patient?

2021 ◽  
pp. 107815522110381
Author(s):  
Esra Özyurt ◽  
Serhat Özçelik ◽  
Heves Sürmeli ◽  
Mehmet Çelik ◽  
Murat Ayhan ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Side Effects ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Host Cells ◽  
Immunoglobulin G4 ◽  
Programmed Cell Death 1 ◽  
Recurrent Renal Cell Carcinoma

Introduction Nivolumab is a human immunoglobulin G4 monoclonal antibody that inhibits programmed cell death-1 activity by binding to the programmed cell death-1 receptors. Cancer cells express increased number of programmed cell death-1 ligands and this allows them to escape the cytotoxic effects of the T cells. Therefore, the negative programmed cell death-1 receptor signal regulates T-cell proliferation and activation is disrupted. However, this change in the activity of the T cells can cause them to lose their ability to recognize host cells. The immune response enabled by these agents has led to side effects, commonly known as “immune-related adverse events.” Case report We report a case of a 66-year-old male patient who was treated with nivolumab for recurrent renal cell carcinoma presented with hepatitis and adrenalitis. Three weeks after starting nivolumab, the patient had abdominal pain and weakness, and then aspartate and alanine transaminase levels were found to be elevated. Management and outcome Hepatitis was predicted to be due to nivolumab, because other causes were excluded. He started using oral methylprednisolone and then, hepatitis improved. However, while receiving methylprednisolone treatment, fludrocortisone was started with the pre-diagnosis of adrenalitis due to the persistence of fatigue, weakness, and hyponatremia and hyperkalemia. With both treatments, the patient's symptoms and sodium and potassium level returned to normal. Discussion This case emphasizes the need for patient's education and awareness of immune-related adverse events, and the importance of understanding the management of life-threatening complications of the checkpoint inhibitors, because these side effects require prompt recognition and treatment.

scholarly journals Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

2012 ◽  
Vol 209 (6) ◽  
pp. 1201-1217 ◽  
Author(s):  
Tadashi Yokosuka ◽  
Masako Takamatsu ◽  
Wakana Kobayashi-Imanishi ◽  
Akiko Hashimoto-Tane ◽  
Miyuki Azuma ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Cell Activation ◽  
Tyrosine Phosphatase ◽  
Cell Receptor ◽  
Programmed Cell Death 1

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1–mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain–containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1–TCR colocalization within microclusters is required for efficient PD-1–mediated suppression. This inhibitory mechanism also functions in PD-1hi T cells generated in vivo and can be overridden by a neutralizing anti–PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

scholarly journals Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro

2020 ◽  
Vol 21 (7) ◽  
pp. 2399
Author(s):  
Woan Ting Tay ◽  
Yi-Hsien Fang ◽  
Suet Theng Beh ◽  
Yen-Wen Liu ◽  
Ling-Wei Hsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
T Cell ◽  
T Lymphocytes ◽  
Programmed Cell Death ◽  
T Cell Response ◽  
Tumor Bearing ◽  
Cd8 T Lymphocytes ◽  
Programmed Cell Death 1

Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.

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