An Interleukin-1 Signature in Breast Cancer Treated with Interleukin-1 Receptor Blockade: Implications for Treating Cytokine Release Syndrome of Checkpoint Inhibitors

Dinarello, Charles A.

doi:10.1158/0008-5472.can-18-2225

Cited by 23 publications

(24 citation statements)

References 11 publications

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“…Administration of anakinra prevented breast cancer progression in humanized mouse model. Moreover, a pilot clinical trial wherein 11 patients with Her2 − metastatic breast cancer were treated with daily subcutaneous Anakinra for a median duration of 4 months, in combination with one of the standard chemotherapeutics, demonstrated that high risk Her2 − breast cancer patients would benefit from reducing levels of IL-1β and treatment with anakinra (45, 46). Excitingly, a recent phase three clinical trial (CANTOS) (45) demonstrated that an inhibitory antibody targeting IL-1β (canakinumab) could significantly reduce the incidence and mortality of lung cancer.…”

Section: Il-1βmentioning

confidence: 99%

IL-1 Family Members in Cancer; Two Sides to Every Story

2019

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The IL-1 family of cytokines currently comprises of seven ligands with pro-inflammatory activity (IL-1α and IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) as well as two ligands with anti-inflammatory activity (IL-37, IL-38). These cytokines are known to play a key role in modulating both the innate and adaptive immunes response, with dysregulation linked to a variety of autoimmune and inflammatory diseases. Given the increasing appreciation of the link between inflammation and cancer, the role of several members of this family in the pathogenesis of cancer has been extensively investigated. In this review, we highlight both the pro- and anti-tumorigenic effects identified for almost all members of this family, and explore potential underlying mechanisms accounting for these divergent effects. Such dual functions need to be carefully assessed when developing therapeutic intervention strategies targeting these cytokines in cancer.

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Section: Il-1βmentioning

confidence: 99%

IL-1 Family Members in Cancer; Two Sides to Every Story

2019

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“…Wu et al analyzed 149 primary breast cancer tissues and found a correlation between overexpression of IL-1β, but not IL-1α, and breast cancer staging. IL-1β expression was mediated by malignant cell-membrane-associated TGF-β in dendritic cells (DC) and monocytes, and neutralizing TGF-β and IL-1β prevented cancer progression in humanized model mice [ 68 , 69 ]. Moreover, both IL-1β and IL-1RI were found to be upregulated in a cancer mouse model with bone metastases, and their blockage with anakinra decreased tumor size and metastases [ 70 ].…”

Section: Il-1 Dysregulation and Its Contribution To Cancer And Tumorimentioning

confidence: 99%

The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice

2018

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Interleukin-1 (IL-1) has long been known to be a key mediator of immunity and inflammation. Its dysregulation has been implicated in recent years in tumorigenesis and tumor progression, and its upregulation is thought to be associated with many tumors. Overexpression of the IL-1 agonists IL-1a and IL-1b has been shown to promote tumor invasiveness and metastasis by inducing the expression of angiogenic genes and growth factors. IL-1 blockers such as anakinra and canakinumab are already approved and widely used for the treatment of some autoimmune and autoinflammatory diseases and are currently being tested in preclinical and human clinical trials for cancer therapy. In this paper we review the most recent discoveries regarding the association between IL-1 dysregulation and cancer and present the novel IL-1 blockers currently being tested in cancer therapy and their corresponding clinical trials.

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“…Both IL-1α and IL-1β activate the same IL-1 receptor, (a dimer of IL-1R1 and IL-1RAcP), while IL-1α is a membrane-bound protein and IL-1β is a soluble protein [36]. IL-1β promotes these effects through the activation of NFκB p65 and MAPK-ERK pathways, resulting in the release of cytokines [37–40]. Similar to our published studies, which showed that OSM is important for osteolytic breast cancer metastasis to bone [19], IL-1β also stimulates the development of bone metastases [41].…”

Section: Introductionmentioning

confidence: 99%

HIGH expression of OSM and IL-6 are associated with decreased breast cancer survival: synergistic induction of IL-6 secretion by OSM and IL-1β

et al. 2019

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Chronic inflammation has been recognized as a risk factor for the development and maintenance of malignant disease. Cytokines such as interleukin-6 (IL-6), oncostatin M (OSM), and interleukin-1 beta (IL-1β) promote the development of both acute and chronic inflammation while promoting in vitro metrics of breast cancer metastasis. However, anti-IL-6 and anti-IL-1β therapeutics have not yielded significant results against solid tumors in clinical trials. Here we show that these three cytokines are interrelated in expression. Using the Curtis TCGA™ dataset, we have determined that there is a correlation between expression levels of OSM, IL-6, and IL-1β and reduced breast cancer patient survival ( r = 0.6, p = 2.2 x 10 −23 ). Importantly, we confirm that OSM induces at least a 4-fold increase in IL-6 production from estrogen receptor-negative (ER−) breast cancer cells in a manner that is dependent on STAT3 signaling. Furthermore, OSM induces STAT3 phosphorylation and IL-1β promotes p65 phosphorylation to synergistically induce IL-6 secretion in ER− MDA-MB-231 and to a lesser extent in ER+ MCF7 human breast cancer cells. Induction may be reduced in the ER+ MCF7 cells due to a previously known suppressive interaction between ER and STAT3. Interestingly, we show in MCF7 cells that ER’s interaction with STAT3 is reduced by 50% through both OSM and IL-1β treatment, suggesting a role for ER in mitigating STAT3-mediated inflammatory cascades. Here, we provide a rationale for a breast cancer treatment regime that simultaneously suppresses multiple targets, as these cytokines possess many overlapping functions that increase metastasis and worsen patient survival.

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An Interleukin-1 Signature in Breast Cancer Treated with Interleukin-1 Receptor Blockade: Implications for Treating Cytokine Release Syndrome of Checkpoint Inhibitors

Abstract: In this issue of Cancer Research, Wu and colleagues show that IL1b orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist.

Cited by 23 publications

References 11 publications

IL-1 Family Members in Cancer; Two Sides to Every Story

IL-1 Family Members in Cancer; Two Sides to Every Story

The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice

HIGH expression of OSM and IL-6 are associated with decreased breast cancer survival: synergistic induction of IL-6 secretion by OSM and IL-1β

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