IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia: An update

Oliveira, Mariana L.; Akkapeddi, Padma; Ribeiro, Daniel; Melão, Alice; Barata, João T.

doi:10.1016/j.jbior.2018.09.012

Cited by 72 publications

(52 citation statements)

References 123 publications

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“…An anti-IL-7 receptor (IL-7Rα) antibody, B12, has also recently been described to induce potent NK cell-mediated ADCC against T-ALL (177). Studies previously showed that IL-7 is an important factor in the progression of T-ALL, enhancing cell expansion and survival (248), making it an attractive target for antibody therapy. In addition to stimulating NK cell ADCC, B12 appears to be rapidly internalized and trafficked into lysosomes of leukemic cells, demonstrating its additional therapeutic potential, such as for intracellular drug delivery.…”

Section: Mabs In Pre-clinical Development-targeting Tumor Antigens Fomentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Mabs In Pre-clinical Development-targeting Tumor Antigens Fomentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…5a, far left panel). Not surprisingly, given the high frequency of Notch activating mutations [3,26] and the role of IL-7 in T-ALL, this profile was associated with increased Notch activation and increased availability to respond to IL-7, as indicated by higher average expression of Notch1 and its targets Hes1 and IL-7r, respectively (Fig. 5a, left, right, and far right panels).…”

Section: Gene Expression Profiling Reveals a Notch/il-7/ Skp2 Signatumentioning

confidence: 95%

“…2c and S2B), suggesting Notch-independent Skp2 regulation. As the culture conditions included IL-7, a cytokine required for T-cells survival and proliferation and involved in p27 Kip1 regulation [24][25][26], we measured the distinct contribution of IL-7 and Notch activation to Skp2 expression. Skp2 expression and thymocyte mitogenic activity were sustained above basal level by IL-7 alone and were significantly upregulated in the presence of Notch signaling ( Fig.…”

Section: Skp2 Expression In Thymocytes Is Upregulated By Notch Signalmentioning

confidence: 99%

Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL

et al. 2019

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Timed degradation of the cyclin-dependent kinase inhibitor p27 Kip1 by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of TALL. Here, we determined that SKP2 function is relevant for TALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human TALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27 Kip1 pathway plays a unique role in TALL development and provide a proof-ofconcept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).

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“…The deregulation of IL7/IL7R signaling can promote cancer development [129]. In particular, this deregulation is associated with leukemogenesis, e.g., acute lymphoblastic leukemia (ALL) of T-and B-cell origin development [130,131] and chronic lymphocytic leukemia [132]. To target lymphoblastic cancer cells, DAB389IL7, was constructed.…”

Section: Targeting Interleukin-7 Receptor (Il-7r)mentioning

confidence: 99%

Targeting Receptors on Cancer Cells with Protein Toxins

Antignani¹,

Ho²,

Bilotta³

et al. 2020

Biomolecules

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Cancer cells frequently upregulate surface receptors that promote growth and survival. These receptors constitute valid targets for intervention. One strategy involves the delivery of toxic payloads with the goal of killing those cancer cells with high receptor levels. Delivery can be accomplished by attaching a toxic payload to either a receptor-binding antibody or a receptor-binding ligand. Generally, the cell-binding domain of the toxin is replaced with a ligand or antibody that dictates a new binding specificity. The advantage of this “immunotoxin” approach lies in the potency of these chimeric molecules for killing cancer cells. However, receptor expression on normal tissue represents a significant obstacle to therapeutic intervention.

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IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia: An update

Cited by 72 publications

References 123 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL

Targeting Receptors on Cancer Cells with Protein Toxins

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