Targeting the JAK/STAT Pathway in T Cell Lymphoproliferative Disorders

Shouse, Geoffrey; Nikolaenko, Liana

doi:10.1007/s11899-019-00545-5

Cited by 19 publications

(21 citation statements)

References 67 publications

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“…Thus, in addition to NK cell stimulation, the treatment could be beneficial against disease in combination with additional drugs such as dexamethasone, which the authors reported to have an additive effect with B12 (177). It is also possible that blocking pathways that were reported to interfere with T-ALL progression using small molecule inhibitors, such as ones targeting JAK/STAT signaling pathways, may also synergize well with anti IL-7Rα mAb treatments (249). Moreover, a recent report showed that NK cells from T-ALL patients have reduced expression of activating receptors and reduced terminal differentiation, which may be bypassed by preactivation of autologous NK cells with IL-12, IL-15, and IL-18 (250).…”

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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“…Trials are underway to determine the efficacy of ruxolitinib in other myeloproliferative diseases, including chronic neutrophilic leukaemia and atypical CML (both often associated with mutations in colony-stimulating factor-3 receptor), as well as AML and T-cell lymphoproliferative disorders. 30 , 31 …”

Section: A Brief Overview Of the Jak Pathway And Its Relevance To Haementioning

confidence: 99%

Therapeutic targeting of JAKs: from hematology to rheumatology and from the first to the second generation of JAK inhibitors

Βertsias

2020

MJR

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Several cytokines and growth factors, as well as their downstream signalling pathways, are implicated in the pathogenesis of haematological and immune-mediated diseases. These mediators act through binding to their cognate receptor and activation of one or more of the four Janus family tyrosine kinases (JAKs). Gene knock-out studies together with evidence from patients carrying activating mutant forms of JAKs (eg, JAK2 V617F in myeloproliferative disorders) provided strong rationale for the development of JAK inhibitors. Based on encouraging preclinical data showing the capacity of JAK inhibitors to suppress the signalling from multiple cytokines, an extensive drug development program was set out, with the initial successful introduction of tofacitinib, baricitinib and ruxolitinib in various chronic rheumatic and myeloproliferative diseases, respectively. Importantly, advancements with the design of next-generation, hyper-selective JAK inhibitors hold promise for the better control of inflammation, while reducing the risk for harms, in an expanding spectrum of medical disorders.

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“…194 Cases harbouring the STAT3-JAK2 fusion show phosphorylation of STAT5, and might be sensitive to JAK inhibitors. 201,202 STAT3 mutations and SOCS1 deletion are other recurrent alterations found essentially in CD4+ cases. 161,194 Other genetic aberrations include loss-of-function mutations in epigenetic modifier genes (TET2, DNMT3A, and KMT2D) and structural alterations of IL2 in CD8+ cases.…”

Section: Molecular Geneticsmentioning

confidence: 99%

Recent advances in upper gastrointestinal lymphomas: molecular updates and diagnostic implications

2020

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Approximately one‐third of extranodal non‐Hodgkin lymphomas involve the gastrointestinal (GI) tract, with the vast majority being diagnosed in the stomach, duodenum, or proximal small intestine. A few entities, especially diffuse large B‐cell lymphoma and extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue, represent the majority of cases. In addition, there are diseases specific to or characteristic of the GI tract, and any type of systemic lymphoma can present in or disseminate to these organs. The recent advances in the genetic and molecular characterisation of lymphoid neoplasms have translated into notable changes in the classification of primary GI T‐cell neoplasms and the recommended diagnostic approach to aggressive B‐cell tumours. In many instances, diagnoses rely on morphology and immunophenotype, but there is an increasing need to incorporate molecular genetic markers. Moreover, it is also important to take into consideration the endoscopic and clinical presentations. This review gives an update on the most recent developments in the pathology and molecular pathology of upper GI lymphoproliferative diseases.

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Targeting the JAK/STAT Pathway in T Cell Lymphoproliferative Disorders

Cited by 19 publications

References 67 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 JAKs: from hematology to rheumatology and from the first to the second generation of JAK inhibitors

Recent advances in upper gastrointestinal lymphomas: molecular updates and diagnostic implications

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