Clinical Grade Regulatory CD4+ T Cells (Tregs): Moving Toward Cellular-Based Immunomodulatory Therapies

Duggleby, Richard C.; Danby, Robert; Madrigal, J. Alejandro; Saudemont, Aurore

doi:10.3389/fimmu.2018.00252

Cited by 64 publications

(73 citation statements)

References 130 publications

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“…In addition, CTLA-4 is shown to be important for regulatory T cell (Treg) function. Tregs control functions of the effector T cells, and thus crucially maintain peripheral tolerance [ 20 ]. Unlike effector T cells, Tregs constitutively express CTLA-4 to exert their immune suppression [ 21 , 22 ].…”

Section: Immune Checkpoints and Hepatocellular Carcinomamentioning

confidence: 99%

Immune checkpoint therapy in liver cancer

Jin

Zhu

et al. 2018

J Exp Clin Cancer Res

289

196

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Immune checkpoints include stimulatory and inhibitory checkpoint molecules. In recent years, inhibitory checkpoints, including cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death ligand 1 (PD-L1), have been identified to suppress anti-tumor immune responses in solid tumors. Novel drugs targeting immune checkpoints have succeeded in cancer treatment. Specific PD-1 blockades were approved for treatment of melanoma in 2014 and for treatment of non-small-cell lung cancer in 2015 in the United States, European Union, and Japan. Preclinical and clinical studies show immune checkpoint therapy provides survival benefit for greater numbers of patients with liver cancer, including hepatocellular carcinoma and cholangiocarcinoma, two main primary liver cancers. The combination of anti-PD-1/PD-L1 with anti-CTLA-4 antibodies is being evaluated in phase 1, 2 or 3 trials, and the results suggest that an anti-PD-1 antibody combined with locoregional therapy or other molecular targeted agents is an effective treatment strategy for HCC. In addition, studies on activating co-stimulatory receptors to enhance anti-tumor immune responses have increased our understanding regarding this immunotherapy in liver cancer. Epigenetic modulations of checkpoints for improving the tumor microenvironment also expand our knowledge of potential therapeutic targets in improving the tumor microenvironment and restoring immune recognition and immunogenicity. In this review, we summarize current knowledge and recent developments in immune checkpoint-based therapies for the treatment of hepatocellular carcinoma and cholangiocarcinoma and attempt to clarify the mechanisms underlying its effects.

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Section: Immune Checkpoints and Hepatocellular Carcinomamentioning

confidence: 99%

Immune checkpoint therapy in liver cancer

Jin

Zhu

et al. 2018

J Exp Clin Cancer Res

289

196

View full text Add to dashboard Cite

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“…In addition, Th22 and Th9, two novel subsets of effector T cells, were discovered in succession. Although each subset of CD4+ T cells can secrete a variety of cytokines and a cytokine can be secreted by several subsets of CD4+ T cells, each subgroup has characteristic inflammatory cytokines [ 5 – 9 ]. Th1, Th2, Th9, Th17, Th22, and Treg cells are involved in inflammatory responses and immune regulation mainly through the secretion of interferon- (IFN-) γ , IL-4, IL-9, IL-17, IL-22, and IL-35, respectively.…”

Section: Introductionmentioning

confidence: 99%

Circulating Th1, Th2, Th9, Th17, Th22, and Treg Levels in Aortic Dissection Patients

Wang

et al. 2018

Mediators of Inflammation

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Background Previous studies demonstrated that the subsets of CD4+ T helper (Th) cells are closely related to vascular diseases, including atherosclerosis and hypertension. This study is aimed at investigating the circulating Th1, Th2, Th9, Th17, Th22, and Treg levels in aortic dissection (AD) patients. Methods Blood samples from AD (n = 56) and non-AD (NAD, n = 24) patients were collected, and the circulating levels of Th1, Th2, Th9, Th17, Th22, and Treg cells and their transcription factors and functional cytokines were measured by flow cytometric analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assays, respectively. In addition, the human aortic vascular smooth muscle cells (HASMCs) were treated with saline, angiotensin II (Ang II), or plasma from AD patients. Results Compared with the levels in the NAD group, the Th1, Th9, Th17, Th22, and their transcription factor levels were increased and the Th2, Treg, and their transcription factor levels exhibited a decreasing trend in AD patients. In addition, higher IFN-γ, IL-9, IL-17, and IL-22 levels and lower IL-4 and IL-35 levels were observed in AD patients. Simple linear regression analysis and binary logistic regression analysis suggested that Th1/IFN-γ, IL-9, Th17/IL-17, and Th22/IL-22 positively regulated the occurrence of AD, while Th2/IL-4 and Treg/IL-35 negatively regulated the occurrence of AD. Plasma from AD patients further increased Bax mRNA levels but decreased Bcl2 and α-SMA mRNA levels in Ang II-treated HASMCs. Conclusions Changes in Th1, Th2, Th9, Th17, Th22, and Treg activity are associated with the onset of AD. Different subsets of CD4+ T cells play different roles in the presence of AD.

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“…Engineering Treg cells with TCRs is a promising approach but limitations occur due to MHC-restrictions. Alloantigen-reactive Treg cells can be expanded through donor APCs, such as dendritic cells, PBMCs, and B cells ( 103 ). Compared to Treg cells engineered with TCRs (TCR-Treg), CAR-modified Treg (CAR-Treg) cells engineered in a non-MHC restricted manner have the advantage of widespread application.…”

Section: Development Over Last Decadementioning

confidence: 99%

The Next Frontier of Regulatory T Cells: Promising Immunotherapy for Autoimmune Diseases and Organ Transplantations

Terry

2020

Front. Immunol.

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BACKGROUND OF REGULATORY T CELLS Naturally occurring CD4 + CD25 high regulatory T (Treg) cells maintain peripheral self-tolerance in rodents and humans (1, 2). In 1995, Sakaguchi and colleagues demonstrated that adoptive transfer of a subset of CD4 + T cells expressing the IL-2 receptor α-chain (CD25) prevented autoimmunity (1). CD4 + CD25 high T cells constitute 5 to 10% of CD4 + T cells in the blood (3) and they are able to maintain immunologic self-tolerance and transplantation tolerance by actively suppressing self-reactive, alloantigen-reactive lymphocytes. Treg cells prevent activation and expansion of auto-reactive T cells that escape clonal deletion in the thymus. Treg cell development and function is controlled by the transcription factor Foxp3, however defects can lead to autoimmune and inflammatory syndromes in humans and mice (4).

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Clinical Grade Regulatory CD4+ T Cells (Tregs): Moving Toward Cellular-Based Immunomodulatory Therapies

Cited by 64 publications

References 130 publications

Immune checkpoint therapy in liver cancer

Immune checkpoint therapy in liver cancer

Circulating Th1, Th2, Th9, Th17, Th22, and Treg Levels in Aortic Dissection Patients

The Next Frontier of Regulatory T Cells: Promising Immunotherapy for Autoimmune Diseases and Organ Transplantations

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