DFF40 deficiency in cancerous T cells is implicated in chemotherapy drug sensitivity and resistance through the regulation of the apoptotic pathway

Dysregulation of either the extrinsic or intrinsic apoptotic pathway can lead to various diseases including immune disorders and cancer. In addition to its role in the extrinsic apoptotic pathway, caspase-8 plays nonapoptotic functions and is essential for T cell homeostasis. The pro-apoptotic BH3-only Bcl-2 family member Bim is important for the intrinsic apoptotic pathway and its inactivation leads to autoimmunity that is further exacerbated by loss of function of the death receptor Fas. We report that inactivation of caspase-8 in T cells of Bim−/− mice restrained their autoimmunity and extended their life span. We show that, similar to caspase-8−/− T cells, Bim−/− T cells that also lack caspase-8 displayed elevated levels of necroptosis and that inhibition of this cell death process fully rescued the survival and proliferation of these cells. Collectively, our data demonstrate that inactivation of caspase-8 suppresses the survival and proliferative capacity of Bim−/− T cells and restrains autoimmunity in Bim−/− mice.

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Identification of an Essential IL15-STAT1-IRX3 Prosurvival Pathway in T Lymphocytes with Therapeutic Implications

10.1101/178939 ◽

2017 ◽

Author(s):

Stephan P. Persengiev

Keyword(s):

T Cells ◽

Transcription Factor ◽

T Lymphocytes ◽

Neural Development ◽

Immune Cell ◽

Apoptotic Pathway ◽

Therapeutic Implications ◽

Survival Pathway ◽

Homeobox Transcription Factor ◽

Cell Death Mechanisms

IRX3 homeobox transcription factor plays a role in neural development and in the pathogenesis of obesity and insulin resistance. T lymphocytes play an essential role in the pathogenesis of obesity and their expansion and differentiation is a tightly controlled process. Circulating cytokines trough activation of cell death mechanisms controls the number of CD4 and CD8 T cells, and failure to activate apoptosis is considered the main cause for their uncontrolled expansion. Here, the identification an essential anti-apoptotic pathway in T lymphocytes is presented, whereby IL-15 activation of Stat/Jak signaling cascade leads to induction of the IRX3 expression. IRX3, in turn, promotes T cells survival and self-renewal, at least partially, by controlling the expression of T-bet transcription factor eomesodermin (EOMES). The Stat/Jak signaling inhibition by Jak inhibitor 1 suppresses IRX3 transcription in T lymphocytes and tumor cell lines and increases apoptosis after growth factor deprivation. Our results demonstrate that IRX3 is essential in T lymphocytes differentiation and reveal that the IL-15-dependent IRX3 pro-survival pathway provides potential therapeutic target for regulation of T cell proliferation that has implications for immune cell malignancies, obesity and autoimmune diseases.

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Preparation and Performance of Chemotherapy Drug-Loaded Graphene Oxide-Based Nanosheets That Target Ovarian Cancer Cells via Folate Receptor Mediation

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2021.3080 ◽

2021 ◽

Vol 17 (5) ◽

pp. 960-970

Author(s):

Jing Wang ◽

Shiyu Han ◽

Zhanteng Zhang ◽

Jiao Wang ◽

Guangmei Zhang

Keyword(s):

Ovarian Cancer ◽

Graphene Oxide ◽

Folate Receptor ◽

Target Therapy ◽

The Body ◽

Ovarian Cancer Cells ◽

Therapeutic Effects ◽

Folate Binding Protein ◽

Apoptotic Pathway ◽

Chemotherapy Drug

Graphene oxide (GO) is one of the most popular nanomaterials that widely used to achieve effective cancer treatment. In this study, a novel, folic acid-decorated graphene oxide (FA-GO)-mediated drug delivery system was synthesized by loading the chemotherapy drug cisplatin (CDDP) or paclitaxel (PTX) to the large surface area of GO for ovarian cancer target therapy. In vitro study showed that the therapeutic effects of FA-GO-CDDP or FA-GO-PTX were increased with folate-binding protein (FBP) expression levels. The GO-CDDP or GO-PTX modified with FA enhanced cancer cell death by promoting DNA damage, ROS production, and apoptotic pathway activation. In vivo anticancer study demonstrated that FA-GO-CDDP nanosheets showed excellent therapeutic performance and attenuated the body weight loss evoked by CDDP treatment. Our results indicate that the chemotherapy agent-loaded FA-GO nanosheets have high potential therapeutic effects against FBP high expressing ovarian cancer.

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The Apoptotic Pathway Contributing to the Deletion of Naive CD8 T Cells during the Induction of Peripheral Tolerance to a Cross-Presented Self-Antigen

The Journal of Immunology ◽

10.4049/jimmunol.180.8.5275 ◽

2008 ◽

Vol 180 (8) ◽

pp. 5275-5282 ◽

Cited By ~ 14

Author(s):

William L. Redmond ◽

Cheng-Hong Wei ◽

Huub T. C. Kreuwel ◽

Linda A. Sherman

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Peripheral Tolerance ◽

Apoptotic Pathway ◽

Self Antigen

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Idiopathic CD4 T Cell Lymphocytopenia: A Case of Overexpression of PD-1/PDL-1 and CTLA-4

Infectious Disease Reports ◽

10.3390/idr13010009 ◽

2021 ◽

Vol 13 (1) ◽

pp. 72-81

Author(s):

Gaurav Kumar ◽

Heidy Schmid-Antomarchi ◽

Annie Schmid-Alliana ◽

Michel Ticchioni ◽

Pierre-Marie Roger

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Ex Vivo ◽

Cd4 T Cell ◽

Apoptotic Pathway ◽

Cell Functions ◽

Inhibitory Molecules ◽

Cd4 T Cell Count ◽

Costimulatory Pathway

Idiopathic CD4 T cell lymphocytopenia (ICL) is a rare entity characterized by CD4 T cell count of <300 cells/mm3 along with opportunistic infection for which T cell marker expression remains to be fully explored. We report an ICL case for which T lymphocyte phenotype and its costimulatory molecules expression was analyzed both ex vivo and after overnight stimulation through CD3/CD28. The ICL patient was compared to five healthy controls. We observed higher expression of inhibitory molecules PD-1/PDL-1 and CTLA-4 on CD4 T cells and increased regulatory T cells in ICL, along with high activation and low proliferation of CD4 T cells. The alteration in the expression of both the costimulatory pathway and the apoptotic pathway might participate to down-regulate both CD4 T cell functions and numbers observed in ICL.

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Sirolimus is effective in autoimmune lymphoproliferative syndrome-type III: A pedigree case report with homozygous variation PRKCD

International Journal of Immunopathology and Pharmacology ◽

10.1177/20587384211025934 ◽

2021 ◽

Vol 35 ◽

pp. 205873842110259

Author(s):

Hao Gu ◽

Zhenping Chen ◽

Jie Ma ◽

Jing Wang ◽

Rui Zhang ◽

...

Keyword(s):

T Cells ◽

Clinical Manifestations ◽

Autoimmune Lymphoproliferative Syndrome ◽

Apoptotic Pathway ◽

Type Iii ◽

Safety Mechanism ◽

Kinase C ◽

Clinical Control ◽

Immature B Cells ◽

Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) usually presents in childhood with fever, nonmalignant splenomegaly, and lymphadenopathy along with cytopenia, which is caused by mutations in the FAS apoptotic pathway. The TCRαβ + CD4/CD8 double-negative T cells (DNT), one of required criteria of ALPS, will rise markedly in ALPS. Human Protein kinase C delta (PRKCD) deficiency (OMIM # 615559) was recently identified to be causative for an ALPS-type III with significant B-cell proliferation particularly of immature B cells. We report a pedigree homozygous variation of PRKCD gene (c.36T>G, p. Y12X) which presented with refractory cytopenia, splenomegaly, and polarization of DNT/regulatory T cells (Treg) axis. After repeated recurrence, the patient was treated with mTOR inhibitor sirolimus, which had a safety mechanism and specifically rebalance the DNT/Treg axis. The patient’s hemoglobin and clinical condition improved gradually by the application of sirolimus (1.5 mg/m2, actual blood concentration 4.27–10.3 ng/l). Homozygous variation in PRKCD may lead to typical ALPS clinical manifestations. Targeting DNT/Treg axis, use of sirolimus in such patients may help to achieve good clinical control.

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The immunomodulatory properties of the HDAC6 inhibitor ACY241 supports robust anti-tumor response in NSCLC when coupled with the chemotherapy drug Oxaliplatin

10.1101/2021.10.01.462824 ◽

2021 ◽

Author(s):

Arup Bag ◽

Andrew Schultz ◽

Saloni Bhimani ◽

William Dominguez ◽

Ling Cen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Rna Sequencing ◽

Tumor Response ◽

Lung Tumor ◽

Potential Contribution ◽

Chemotherapy Drug ◽

Hdac6 Inhibitor ◽

Immunomodulatory Properties ◽

Cell Effector

Background: Durable treatments that benefit a wide pool of patients remain elusive for Non-small cell lung cancer (NSCLC). The success of immunotherapy in a subset of NSCLC patients highlights the potential contribution of immune response to anti-tumor immunity while underscoring a need for broadly applicable therapeutic strategies. HDAC inhibitors are a promising class of drugs whose immunomodulatory properties are now being appreciated. In the present study, we evaluated the effects of the HDAC6 inhibitor, ACY241 on lung tumor immune compartment with the goal of understanding the scope of its immunomodulatory properties and its therapeutic potential in combination with Oxaliplatin. Methods: Lung adenocarcinoma-bearing mice were treated with ACY241 or vehicle after which the proportions and phenotype of tumor-associated T cells and macrophages were evaluated by comprehensive flow cytometric analysis. Bulk RNA-sequencing was also conducted on both cellular subsets to interrogate the transcriptomic changes associated with ACY241 treatment relative to vehicle controls. In vivo drug efficacy study was performed by administration of ACY241 and/or Oxaliplatin and assessing tumor growth and survival of tumor-bearing mice. Ex vivo functional studies was performed to assess tumor-associated T cell effector function as it correlates with measured outcomes. Results: We demonstrate that ACY241 promotes increased presence of T and NK cells in the lung tumors of treated mice. The tumor-associated T cells under ACY241 treatment displayed enhanced activation, proliferation, and effector profile. In addition, tumor-associated macrophages exhibited increased expression of MHC and co-stimulatory molecules while expression of inhibitory ligands were reduced. RNA-sequencing of both tumor-associated T cells and macrophages revealed significant genomic changes in both subsets that is consistent with ACY241-mediated enhancement of immune priming. These broad immunomodulatory properties of ACY241 were associated with significantly enhanced tumor-associated T cell effector functionality, robust anti-tumor response, and significantly prolonged survival of NSCLC-bearing mice when combined with the chemotherapy drug Oxaliplatin. Conclusion: Collectively, our studies highlight the broad immunomodulatory effect of ACY241 as a promising HDAC6 inhibitor which coupled with Oxaliplatin promotes robust therapeutic outcomes in a pre-clinical model of NSCLC, providing compelling rationale for the clinical testing of this novel combinatorial regimen in NSCLC.

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