164. Allogeneic Lymphocyte-Licensed DCs Expand TCR/CAR-Engineered T Cells, Which Are Insensitive To Oxidative Stress and Immunosuppressive Factors

: Cancer immunotherapy endeavours in harnessing delicate strength and specificity of immune system for therapy of different malignancies including colorectal carcinoma. The recent challenge for cancer immunotherapy is to practice and develop molecular immunology tools to create tactics that efficiently and securely boost antitumor reactions. After several attempts of deceptive outcomes, the wave has lastly altered and immunotherapy has become a clinically confirmed treatment for several cancers. Immunotherapeutic methods include administration of antibodies or modified proteins that either block cellular activity or co-stimulate cells through immune control pathways, cancer vaccines, oncolytic bacteria, ex vivo activated adoptive transfer of T cells and natural killer cells. Engineered T cells are used to produce a chimeric antigen receptor (CAR) to treat different malignancies including colorectal carcinoma in a recent decade. Despite considerable early clinical success, CAR-T therapies are associated with some side effects and sometimes display minimal efficacy. It gives special emphasis on the latest clinical evidence with CAR-T technology and also other related immunotherapeutic methods with promising performance, and highlighted how this therapy can affect therapeutic outcome and next upsurge as a key clinical aspect of colorectal carcinoma. In this review we recapitulate the current developments produced to improve the efficacy and specificity of CAR-T therapies in colon cancer.

Download Full-text

Resistance of chimpanzee T cells to human immunodeficiency virus type 1 Tat-enhanced oxidative stress and apoptosis.

Journal of Virology ◽

10.1128/jvi.70.9.6502-6507.1996 ◽

1996 ◽

Vol 70 (9) ◽

pp. 6502-6507 ◽

Cited By ~ 31

Author(s):

A Ehret ◽

M O Westendorp ◽

I Herr ◽

K M Debatin ◽

J L Heeney ◽

...

Keyword(s):

Oxidative Stress ◽

Human Immunodeficiency Virus ◽

T Cells ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Immunodeficiency Virus

Download Full-text

CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00962.2008 ◽

2009 ◽

Vol 296 (3) ◽

pp. H689-H697 ◽

Cited By ~ 30

Author(s):

Karen Y. Stokes ◽

LeShanna Calahan ◽

Candiss M. Hamric ◽

Janice M. Russell ◽

D. Neil Granger

Keyword(s):

Oxidative Stress ◽

T Cells ◽

T Cell ◽

Blood Cell ◽

Cell Function ◽

Inflammatory Responses ◽

Microvascular Dysfunction ◽

Cd40 Ligand ◽

Scid Mice ◽

Endothelial Cell Function

Hypercholesterolemia is associated with phenotypic changes in endothelial cell function that lead to a proinflammatory and prothrombogenic state in different segments of the microvasculature. CD40 ligand (CD40L) and its receptor CD40 are ubiquitously expressed and mediate inflammatory responses and platelet activation. The objective of this study was to determine whether CD40/CD40L, in particular T-cell CD40L, contributes to microvascular dysfunction induced by hypercholesterolemia. Intravital microscopy was used to quantify blood cell adhesion in cremasteric postcapillary venules, endothelium-dependent vasodilation responses in arterioles, and microvascular oxidative stress in wild-type (WT) C57BL/6, CD40-deficient (−/−), CD40L−/−, or severe combined immune deficient (SCID) mice placed on a normal (ND) or high-cholesterol (HC) diet for 2 wk. WT-HC mice exhibited an exaggerated leukocyte and platelet recruitment in venules and impaired vasodilation responses in arterioles compared with ND counterparts. A deficiency of CD40, CD40L, or lymphocytes attenuated these responses to HC. The HC phenotype was rescued in CD40L−/− and SCID mice by a transfer of WT T cells. Bone marrow chimeras revealed roles for both vascular- and blood cell-derived CD40 and CD40L in the HC-induced vascular responses. Hypercholesterolemia induced an oxidative stress in both arterioles and venules of WT mice, which was abrogated by either CD40 or CD40L deficiency. The transfer of WT T cells into CD40L−/− mice restored the oxidative stress. These results implicate CD40/CD40L interactions between circulating cells and the vascular wall in both the arteriolar and venular dysfunction elicited by hypercholesterolemia and identify T-cell-associated CD40L as a key mediator of these responses.

Download Full-text

Novel agents and regimens for hematological malignancies: recent updates from 2020 ASH annual meeting

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01077-3 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Jing-Zhou Hou ◽

Jing Christine Ye ◽

Jeffrey J. Pu ◽

Hongtao Liu ◽

Wei Ding ◽

...

Keyword(s):

New York ◽

T Cells ◽

Annual Meeting ◽

Hematological Malignancies ◽

Novel Agents ◽

Car T Cells ◽

Car T ◽

Bruton Tyrosine Kinase ◽

Engineered T Cells ◽

American Society

AbstractAntibodies and chimeric antigen receptor-engineered T cells (CAR-T) are increasingly used for cancer immunotherapy. Small molecule inhibitors targeting cellular oncoproteins and enzymes such as BCR-ABL, JAK2, Bruton tyrosine kinase, FLT3, BCL-2, IDH1, IDH2, are biomarker-driven chemotherapy-free agents approved for several major hematological malignancies. LOXO-305, asciminib, “off-the-shelf” universal CAR-T cells and BCMA-directed immunotherapeutics as well as data from clinical trials on many novel agents and regimens were updated at the 2020 American Society of Hematology (ASH) Annual Meeting. Major developments and updates for the therapy of hematological malignancies were delineated at the recent Winter Symposium and New York Oncology Forum from the Chinese American Hematologist and Oncologist Network (CAHON.org). This study summarized the latest updates on novel agents and regimens for hematological malignancies from the 2020 ASH annual meeting.

Download Full-text

Oxidative stress response in regulatory and conventional T cells: a comparison between patients with chronic coronary syndrome and healthy subjects

Journal of Translational Medicine ◽

10.1186/s12967-021-02906-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Anna K. Lundberg ◽

Rosanna W. S. Chung ◽

Louise Zeijlon ◽

Gustav Fernström ◽

Lena Jonasson

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Mononuclear Cells ◽

Ex Vivo ◽

Thioredoxin Reductase ◽

Healthy Controls ◽

Antioxidant Genes ◽

Consistent Finding ◽

Coronary Syndrome ◽

Thioredoxin Reductase 1

Abstract Background Inflammation and oxidative stress form a vicious circle in atherosclerosis. Oxidative stress can have detrimental effects on T cells. A unique subset of CD4+ T cells, known as regulatory T (Treg) cells, has been associated with atheroprotective effects. Reduced numbers of Treg cells is a consistent finding in patients with chronic coronary syndrome (CCS). However, it is unclear to what extent these cells are sensitive to oxidative stress. In this pilot study, we tested the hypothesis that oxidative stress might be a potential contributor to the Treg cell deficit in CCS patients. Methods Thirty patients with CCS and 24 healthy controls were included. Treg (CD4+CD25+CD127−) and conventional T (CD4+CD25−, Tconv) cells were isolated and treated with increasing doses of H2O2. Intracellular ROS levels and cell death were measured after 2 and 18 h, respectively. The expression of antioxidant genes was measured in freshly isolated Treg and Tconv cells. Also, total antioxidant capacity (TAC) was measured in fresh peripheral blood mononuclear cells, and oxidized (ox) LDL/LDL ratios were determined in plasma. Results At all doses of H2O2, Treg cells accumulated more ROS and exhibited higher rates of death than their Tconv counterparts, p < 0.0001. Treg cells also expressed higher levels of antioxidant genes, including thioredoxin and thioredoxin reductase-1 (p < 0.0001), though without any differences between CCS patients and controls. Tconv cells from CCS patients were, on the other hand, more sensitive to oxidative stress ex vivo and expressed more thioredoxin reductase-1 than Tconv cells from controls, p < 0.05. Also, TAC levels were lower in patients, 0.97 vs 1.53 UAE/100 µg, p = 0.001, while oxLDL/LDL ratios were higher, 29 vs 22, p = 0.006. Conclusion Treg cells isolated from either CCS patients or healthy controls were all highly sensitive to oxidative stress ex vivo. There were signs of oxidant-antioxidant imbalance in CCS patients and we thus assume that oxidative stress may play a role in the reduction of Treg cells in vivo.

Download Full-text

Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response

Toxicological Sciences ◽

10.1093/toxsci/kfaa022 ◽

2020 ◽

Vol 175 (1) ◽

pp. 64-74 ◽

Cited By ~ 3

Author(s):

Nivedita Banerjee ◽

Hui Wang ◽

Gangduo Wang ◽

M Firoze Khan

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Autoimmune Response ◽

Mediated Effects ◽

Antioxidant Gene Expression ◽

Responsive Element

Abstract Trichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.

Download Full-text

Expression profiling of TCR-engineered T cells demonstrates overexpression of multiple inhibitory receptors in persisting lymphocytes

Blood ◽

10.1182/blood-2013-04-495531 ◽

2013 ◽

Vol 122 (8) ◽

pp. 1399-1410 ◽

Cited By ~ 50

Author(s):

Daniel Abate-Daga ◽

Ken-ichi Hanada ◽

Jeremy L. Davis ◽

James C. Yang ◽

Steven A. Rosenberg ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Tumor Antigen ◽

Expression Profiling ◽

Inhibitory Receptors ◽

Key Points ◽

Engineered T Cells

Key Points Gene expression in TCR-engineered cells resembles that of virus-reactive cells more than native tumor antigen-reactive cells. Persisting TCR gene–engineered T cells are sensitive to PD-L1–PD-1 interaction but CD160-associated impairment is ligand-independent.

Download Full-text