Blocking programmed cell death 1 in combination with adoptive cytotoxic T-cell transfer eradicates chronic myelogenous leukemia stem cells

AbstractAnti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.

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

Journal of Experimental Medicine ◽

10.1084/jem.20112741 ◽

2012 ◽

Vol 209 (6) ◽

pp. 1201-1217 ◽

Cited By ~ 442

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21072399 ◽

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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Programmed Cell Death 1 and Programmed Cell Death Ligands in Extranodal Natural Killer/T Cell Lymphoma: Expression Pattern and Potential Prognostic Relevance

Acta Haematologica ◽

10.1159/000500974 ◽

2019 ◽

Vol 143 (1) ◽

pp. 78-88 ◽

Cited By ~ 3

Author(s):

Hamidah Muhamad ◽

Narittee Suksawai ◽

Thamatorn Assanasen ◽

Chantana Polprasert ◽

Udomsak Bunworasate ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Natural Killer ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Lymphoma Cells ◽

Natural Killer T Cell ◽

Programmed Cell Death 1 ◽

Killer T Cell

The programmed cell death 1/programmed cell death ligands (PD-1/PD-Ls) axis is a potential immune escape mechanism of cancers. However, data on the PD-1/PD-Ls pathway in EBV-associated extranodal natural killer/T cell lymphoma (ENKTL) and its clinical implication are limited. Herein, we characterized PD-1/PD-L expression and its prognosis relevance in 49 ENKTL patients in Thailand. PD-L1 was expressed frequently on both lymphoma cells (61.2%) and stroma (77.5%), whereas PD-L2 expression was more common on lymphoma (63.2%) than stromal cells. PD-1 was positive in 20.5% of stroma, but undetectable on lymphoma cells. There was no association between baseline clinical characteristics and the expression PD-1/PD-Ls. The survival of patients with PD-Ls on tumor cells was poor. For PD-L1-positive versus negative cases, the 2-year event-free survival (EFS) was 42.2 versus 71.8% (p = 0.03) and 2-year overall survival (OS) was 45.4 versus 78.9% (p = 0.02), respectively. Comparing between patients with PD-L2-positive and PD-L2-negative lymphoma, the 2-year EFS was 37.1 versus 82.4% (p = 0.02) and 2-year OS was 45.2 versus 82.4% (p = 0.03), respectively. Neither PD-1 nor PD-Ls expression in the stroma predicted outcomes. In conclusion, PD-Ls were frequently expressed on ENKTL cells and associated with inferior outcomes. Therefore, PD-Ls are potential prognostic biomarkers and the roles of immune checkpoint blockade therapy in ENKTL deserve further investigation.

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Roles for TGF-β and Programmed Cell Death 1 Ligand 1 in Regulatory T Cell Expansion and Diabetes Suppression by Zymosan in Nonobese Diabetic Mice

The Journal of Immunology ◽

10.4049/jimmunol.1001365 ◽

2010 ◽

Vol 185 (5) ◽

pp. 2754-2762 ◽

Cited By ~ 18

Author(s):

Oliver T. Burton ◽

Paola Zaccone ◽

Jenny M. Phillips ◽

Hugo De La Peña ◽

Zoltán Fehérvári ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Regulatory T Cell ◽

Cell Expansion ◽

Diabetic Mice ◽

Nonobese Diabetic ◽

Programmed Cell Death 1 ◽

T Cell Expansion ◽

Nonobese Diabetic Mice

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Programmed cell death ligand‐1 and cytotoxic T cell infiltrates in metastatic cutaneous squamous cell carcinoma of the head and neck

Head & Neck ◽

10.1002/hed.26370 ◽

2020 ◽

Vol 42 (11) ◽

pp. 3226-3234

Author(s):

Stefan Kraft ◽

Shekhar K. Gadkaree ◽

Daniel G. Deschler ◽

Derrick T. Lin ◽

Mai P. Hoang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Cutaneous Squamous Cell Carcinoma ◽

Cytotoxic T Cell

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Decrease of T-cells exhaustion markers programmed cell death-1 and T-cell immunoglobulin and mucin domain-containing protein 3 and plasma IL-10 levels after successful treatment of chronic hepatitis C

Scientific Reports ◽

10.1038/s41598-020-73137-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sylwia Osuch ◽

Tomasz Laskus ◽

Hanna Berak ◽

Karol Perlejewski ◽

Karin J. Metzner ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Chronic Hepatitis ◽

Hepatitis C ◽

T Cell ◽

Liver Fibrosis ◽

Programmed Cell Death ◽

Chronic Hepatitis C ◽

Programmed Cell Death 1 ◽

Advanced Liver Fibrosis

Abstract During chronic hepatitis C virus (HCV) infection, both CD4+ and CD8+ T-cells become functionally exhausted, which is reflected by increased expression of programmed cell death-1 (PD-1) and T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and elevated anti-inflammatory interleukin 10 (IL-10) plasma levels. We studied 76 DAA-treated HCV-positive patients and 18 non-infected controls. Flow cytometry measured pretreatment frequencies of CD4+PD-1+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cells and IL-10 levels measured by ELISA were significantly higher and CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells were significantly lower in patients than in controls. Treatment resulted in significant decrease of CD4+Tim-3+, CD8+Tim-3+, CD4+PD-1+Tim-3+ and CD8+PD-1+Tim-3+ T-cell frequencies as well as IL-10 levels and increase in CD4+PD-1−Tim-3− and CD8+PD-1−Tim-3− T-cells. There were no significant changes in the frequencies of CD4+PD-1+ T-cells, while CD8+PD-1+ T-cells increased. Patients with advanced liver fibrosis had higher PD-1 and lower Tim-3 expression on CD4+T-cells and treatment had little or no effect on the exhaustion markers. HCV-specific CD8+T-cells frequency has declined significantly after treatment, but their PD-1 and Tim-3 expression did not change. Successful treatment of chronic hepatitis C with DAA is associated with reversal of immune exhaustion phenotype, but this effect is absent in patients with advanced liver fibrosis.

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