JAK/STAT disruption induces immuno-deficiency: Rationale for the development of JAK inhibitors as immunosuppressive drugs

Cornez, Isabelle; Yajnanarayana, Sowmya Parampalli; Wolf, Anna Maria; Wolf, Dominik

doi:10.1016/j.mce.2017.01.035

Cited by 31 publications

(21 citation statements)

References 107 publications

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“…Similarly, several mutations have been evidenced in STATs, particularly Stat1, Stat3, and Stat5 [3,152]. Altered immune function is common to many of these mutations, including aberrant cytokine signaling and responsiveness, poor Th1 differentiation, IFN dysregulation, loss of NK cell cytotoxicity, abnormal myeloproliferation, and autoimmunity [63,152,153]. As such, many of the effects that LOF and GOF mutations in JAK-STAT pathway members direct in the cancer context are immune-associated.…”

Section: Dysregulation Of Jak-stat Signaling In Cancermentioning

confidence: 99%

“…The trial was subsequently terminated due to progressive disease in all surviving enrolled patients. In fact, many JAKinibs that have shown promise in preclinical and early patient trials have failed to progress due to high toxicity and off-target immune-suppression, such as the JAK2 inhibitor, AZD1480 [152,208], which was shown to potently suppress both STAT1 and STAT3 signaling [209]. Such reports are increasingly salient, given the importance of retained type I IFN signaling in the TME to the efficacy of checkpoint inhibitors [190,210] that are often utilized in conjunction with JAKinibs, which JAK inhibition is likely to impede.…”

Section: Jak Inhibitionmentioning

confidence: 99%

“…However, while numerous studies using mice models have reported increases in TME infiltration by T cells, suppression of Tregs and MDSCs, and decreased NFκB signaling [221] in tumor bearing animals, curcumin has also been linked to the inhibition of DC activation [222,223]. Interestingly, ruxolitinib has been shown to target other kinases, including those that regulate DC recruitment (ROCK), which is suggested to contribute to the loss of DC activity observed in treated patients [152]. Therefore, it is possible that curcumin exerts the same effect, given it has also been shown to directly inhibit the activation of JAK2 [224].…”

Section: Therapeutic Modulation Of Statsmentioning

confidence: 99%

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JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

427

326

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Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.2 of 26 role in pathogenesis [3]. Yet, despite the seemingly linear order of events, the impact of mutations, selective dimerization, negative pathway regulation, and post-translational modifications of pathway members has branded the JAK-STAT axis a complex signaling cascade, of which many regulatory processes are still poorly understood.STATs have emerged as somewhat of a double-edged sword, being widely explored in the context of cancer. While several members of the STAT family, which encompasses STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 as a whole, have been linked to tumor initiation and progression (STAT3 and STAT5), others are integral in antitumor defense and the maintenance of an effective and long-term immune response (STAT1 and STAT2) through evolutionarily conserved programs [1]. With increasing emphasis on immune-based agents as important therapeutics in the fight against solid tumor growth and spread, understanding the function of STAT specificity, redundancy, and connectedness in cancer is a critical component of achieving immunotherapeutic augmentation and success.Here, we investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense. JAK-STAT Signaling and InterferonsThe presence of stimulatory or inhibitory signals governs the innate and adaptive immune activity that controls both effective immune surveillance and facilitates escape. Such signals determine the fate of plastic immune cells, such as T lymphocytes, and regulate their recruitment, survival, status, and eventual death ...

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Section: Dysregulation Of Jak-stat Signaling In Cancermentioning

confidence: 99%

Section: Jak Inhibitionmentioning

confidence: 99%

Section: Therapeutic Modulation Of Statsmentioning

confidence: 99%

See 1 more Smart Citation

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

427

326

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“…There is also evidence that high Treg numbers predict recurrent SCC in kidney transplant patients (55) and that Tregs directly regulate IL-22 expression via regulation of IL-22producing innate and adaptive immune cells (56). Ruxolitinib has been shown to inhibit dendritic cells, NK cells, and T cells (57); induce long-lasting Treg reduction in myelofibrosis patients (58); and prevent cytokine release syndrome associated with CAR-T therapy, without impairing its antitumor efficacy (59). Promising results are also emerging with JAK inhibition in other IL-22-related hyperproliferative cutaneous conditions, such as psoriasis (60,61).…”

Section: Discussionmentioning

confidence: 99%

Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma

Burgo¹,

Roudiani²,

Chen³

et al. 2018

JCI Insight

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Organ transplant recipients (OTRs) on cyclosporine A (CSA) are prone to catastrophic cutaneous squamous cell carcinoma (SCC). Allograft-sparing, cancer-targeting systemic treatments are unavailable. We have shown increased risk for catastrophic SCC in OTRs via CSA-mediated induction of IL-22. Herein, we found that CSA drives SCC proliferation and tumor growth through IL-22 and JAK/STAT pathway induction. We in turn inhibited SCC growth with an FDA-approved JAK1/2 inhibitor, ruxolitinib. In human SCC cells, the greatest proliferative response to IL-22 and CSA treatment occurred in nonmetastasizing lines. IL-22 treatment upregulated JAK1 and STAT1/3 in A431 SCC cells. JAK/STAT pathway genes were highly expressed in tumors from a cohort of CSA-exposed OTRs and in SCC with high risk for metastasis. Compared with immunocompetent SCC, genes associated with innate immunity, response to DNA damage, and p53 regulation were differentially expressed in SCC from OTRs. In nude mice engrafted with human A431 cells, IL-22 and CSA treatment increased tumor growth and upregulated IL-22 receptor, JAK1, and STAT1/3 expression. Ruxolitinib treatment significantly reduced tumor volume and reversed the accelerated tumor growth. CSA and IL-22 exacerbate aggressive behavior in SCC. Targeting the IL-22 axis via selective JAK/STAT inhibition may reduce the progression of aggressive SCC in OTRs, without compromising immunosuppression.

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“…Basierend auf umfangreichen Studienprogrammen wurden in Deutsch-land 2017 zunächst Baricitinib und Tofacitinib für die RA, zusätzlich 2018 Tofacitinib für PsA und Colitis ulcerosa zugelassen. Das initiale Interesse der Forschung basierte auf der Beobachtung, dass genetische Defekte bei JAKs mit Immundefizienz assoziiert sind [1]. Diese Beobachtung, zusammen mit Erkenntnissen aus der Grundlagenforschung, die zeigten das JAK-vermittelte Signalwege bei der Pathogenese der RA, Psoriasis, PsA, chronisch-entzündlicher Darmerkrankung und anderen Autoimmunerkrankungen eine Rolle spielen [2], führten zur klinischen Ent-wicklung von auf JAK-Inhibition abzielenden Therapien.…”

Section: Introductionunclassified

Sicherheit von JAK-Inhibitoren

Leipe¹

2019

Arthritis und Rheuma

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ZusammenfassungDie zugelassenen Januskinase (JAK)-Inhibitoren Baricitinib und Tofacitinib haben bereits das Armamentarium hochwirksamer Therapien bei rheumatoider Arthritis, Psoriasis-Arthritis und Colitis ulcerosa erweitert. Als Alternative zu Biologika unterscheiden sie sich jedoch durch den Wirkmechanismus (Hemmung intrazellulärer Signalübertragung) und die orale Verfügbarkeit. Die Sicherheit ist jedoch ähnlich gut wie bei Biologika, am häufigsten kommen leichtgradige Infekte der oberen Atemwege vor. Verhältnismäßig seltene, aber spezifische Nebenwirkungen stellen Herpes-Zoster-Infektionen dar. Schwere Infektionen werden nur selten beobachtet. Nicht-infektiöse Nebenwirkungen beinhalten Laborwertveränderungen in Form von Zytopenien, Anstieg von Cholesterin (scheinbar ohne Erhöhung des kardiovaskulären Risikos), selten Leber- und Nierenwert-Erhöhungen sowie vermutlich ein erhöhtes Thromboembolie-Risiko bei bestimmten Risikokonstellationen.

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JAK/STAT disruption induces immuno-deficiency: Rationale for the development of JAK inhibitors as immunosuppressive drugs

Cited by 31 publications

References 107 publications

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Ruxolitinib inhibits cyclosporine-induced proliferation of cutaneous squamous cell carcinoma

Sicherheit von JAK-Inhibitoren

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