CTLA-4: a moving target in immunotherapy

Rowshanravan, Behzad; Halliday, Neil; Sansom, David M.

doi:10.1182/blood-2017-06-741033

Cited by 828 publications

(650 citation statements)

References 136 publications

(127 reference statements)

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“…36 CTLA-4 plays a critical negative regulatory role for T-cell function in the primary immune response. 37 We first found that the percentage of CTLA-4 + CD3 + , CD4 + and CD8 + T cells was significantly higher in patients with AML compared to healthy individuals ( Figure 1A and B). These results are similar to findings from a study of immune checkpoint protein expression on T cells from patients with chronic lymphocytic leukemia (CLL) in which higher numbers of CD4 + and CD8 + T cells with intracellular CTLA-4 were observed in CLL.…”

Section: Resultsmentioning

confidence: 82%

“…CTLA‐4 is a member of a family of immunoglobulin‐related receptors that have both stimulatory and inhibitory roles in T‐cell immunity . CTLA‐4 plays a critical negative regulatory role for T‐cell function in the primary immune response . We first found that the percentage of CTLA‐4 + CD3 + , CD4 + and CD8 + T cells was significantly higher in patients with AML compared to healthy individuals (Figure A and B).…”

Section: Resultsmentioning

confidence: 85%

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Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Chen

Tan

Huang

et al. 2019

Asia-Pac J Clncl Oncology

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Aim Immune suppression based on alternative regulation of immune checkpoint proteins, for example, programmed cell death receptor‐1 (PD‐1) and cytotoxic T lymphocyte–associated molecule‐4 (CTLA‐4), which results in T‐cell exhaustion, contributes to cancer development and progression. In this study, we sought to characterize the distribution of CTLA‐4 and T‐cell lymphocyte activation gene‐3 (LAG‐3) expression on exhausted T cells in different T‐cell subsets from patients with acute myeloid leukemia (AML). Methods The coexpression of CTLA‐4 and LAG‐3 on exhausted CD244+ and CD57+ T cells from the CD3+, CD4+, and CD8+ T‐cell subsets in peripheral blood from 12 patients with newly diagnosed AML was analyzed by multicolor flow cytometry assay. Results A significantly higher percentage of CTLA‐4+CD3+, CD4+ and CD8+ T cells was found in patients with AML. In addition, higher numbers of both CTLA‐4+CD244+ and CTLA‐4+CD57+CD3+ T cells were detected. Interestingly, the increased CTLA‐4+CD244+ T cells were predominantly CD4+ T cells. In contrast, the increased CTLA‐4+CD57+ T cells primarily consisted of the CD8+ T‐cell subset. A high proportion of LAG‐3+ T cells was found in only a few cases with AML; however, a significantly higher proportion of coexpression of CTLA‐4 and LAG‐3 in the CD3+ and CD8+ T‐cell subsets was detected. Conclusion We for the first time observed higher CTLA‐4+CD244+CD4+, CTLA‐4+CD57+CD8+, CTLA‐4+LAG‐3+CD3+ and CTLA‐4+LAG‐3+CD8+ T cells in patients with AML, whereas the upregulated expression of LAG‐3 on T cells was only found in a subset of the cases. These data may provide further information by complementing the heterogeneity of immune checkpoints expression in AML.

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Section: Resultsmentioning

confidence: 82%

Section: Resultsmentioning

confidence: 85%

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Chen

Tan

Huang

et al. 2019

Asia-Pac J Clncl Oncology

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“…A variant of cyclotide MCoTI‐II capable of binding to cytotoxic T lymphocyte‐associated antigen 4 (CTLA‐4) has been developed by the direct evolution method to target metastatic melanoma . CTLA‐4 is a type of immunoglobin receptor molecule expressed by T lymphocytes that serves as a checkpoint for several immune responses. It has been targeted earlier with monoclonal antibodies to elicit an immune‐mediated antitumor response.…”

Section: Cyclotide Scaffold For Anticancer Bioactive Peptidesmentioning

confidence: 99%

Natural and grafted cyclotides in cancer therapy: An insight

Mehta

Dhankhar

Gulati

et al. 2020

Journal of Peptide Science

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Cyclotides is a rapidly growing class of plant‐derived cyclic peptides exhibiting several bioactivities with potential applications in the agricultural and pharmaceutical sectors. Both natural and grafted cyclotides have shown promise in cancer therapy. Approximately 70 natural cyclotides belonging to three plant families (Fabaceae, Rubiaceae, and Violaceae) have shown cytotoxicity against several cancer cell lines. Cyclotides exhibit considerable stability against thermal and enzymatic proteolysis, owing to their unique structure with knotted topology and head to tail cyclization. Further, their small size, high stability, oral bioavailability, and tolerance to amino acid substitution in structural loops make them an ideal platform for designing peptide‐based drugs for cancer. Thus, cyclotides provide ideal scaffolds for bioactive epitope grafting and facilitating drug delivery in cancer treatment. Many anticancer linear peptides have been grafted in cysteine knotted cyclic framework of cyclotide for enhancing their cell permeability across cellular membranes, thereby improving their delivery and pharmacokinetics. The present review comprehensively discusses the distribution, toxicity, and anticancer bioactivity of natural cyclotides. Further, it systematically elaborates on the role and action of epitopes' into grafted cyclotides in targeting cancer. The review also encompasses related patents landscape study and future challenges in peptide‐based cancer therapy.

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“…Although there are questions about the capacity of the intracellular domain of the CTLA‐4 receptor to transduce signals (and some suggestion that the influence of CTLA‐4 binding is limited to its own cycling between cytosolic vesicles and the cell surface), it has also been proposed that CTLA‐4 binding can antagonize the activation signal in a cell‐intrinsic manner by attenuating the PI3K pathway, by activating the protein phosphatase 2A (PP2A) …”

Section: Pi3kδ Downstream Of Checkpoint Receptorsmentioning

confidence: 99%

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

Lim

Okkenhaug

2019

Immunology

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Summary Tumour infiltration by regulatory T (Treg) cells contributes to suppression of the anti‐tumour immune response, which limits the efficacy of immune‐mediated cancer therapies. The phosphoinositide 3‐kinase (PI3K) pathway has key roles in mediating the function of many immune cell subsets, including Treg cells. Treg function is context‐dependent and depends on input from different cell surface receptors, many of which can activate the PI3K pathway. In this review, we explore how PI3Kδ contributes to signalling through several major immune cell receptors, including the T‐cell receptor and co‐stimulatory receptors such as CD28 and ICOS, but is antagonized by the immune checkpoint receptors CTLA‐4 and PD‐1. Understanding how PI3Kδ inhibition affects Treg signalling events will help to inform how best to use PI3Kδ inhibitors in clinical cancer treatment.

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CTLA-4: a moving target in immunotherapy

Cited by 828 publications

References 136 publications

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Natural and grafted cyclotides in cancer therapy: An insight

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

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CTLA-4: a moving target in immunotherapy

Cited by 828 publications

References 136 publications

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Natural and grafted cyclotides in cancer therapy: An insight

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

Contact Info

Product

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Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia