Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment

Nakamura, Kyohei; Kassem, Sahar; Cleynen, Alice; Chrétien, Marie Lorraine; Guillerey, Camille; Putz, Eva Maria; Bald, Tobias; Förster, Irmgard; Vučković, Slavica; Hill, Geoffrey R.; Masters, Seth L.; Chesi, Marta; Bergsagel, P. Leif; Avet-Loiseau, Hervé; Martinet, Ludovic; Smyth, Mark J.

doi:10.1016/j.ccell.2018.02.007

Cited by 173 publications

(137 citation statements)

References 54 publications

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“…Moreover, IL‐18‐deficient mice were shown to be protected in a mouse model of MM, and IL‐18 was proposed to act by modulating CD8 + T‐cell responses and immunosuppressive MDSC generation. This hypothesis was further corroborated by a comprehensive analysis of the transcriptional landscape of the immune microenvironment in MM patients, which revealed a positive correlation between IL‐18 and PMN‐MDSC signature genes and an inverse correlation between the PMN‐MDSC signature and a cytotoxic gene signature . Moreover, serum levels of IL‐18 correlated with stage III disease and were associated with increased levels of angiogenic cytokines such as VEGF and increased mortality in a cohort of 65 newly diagnosed MM patients .…”

Section: Introductionmentioning

confidence: 68%

The emerging roles of inflammasome‐dependent cytokines in cancer development

Gorp

Lamkanfi

2019

EMBO Reports

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In addition to the genomic alterations that occur in malignant cells, the immune system is increasingly appreciated as a critical axis that regulates the rise of neoplasms and the development of primary tumours and metastases. The interaction between inflammatory cell infiltrates and stromal cells in the tumour microenvironment is complex, with inflammation playing both pro‐ and anti‐tumorigenic roles. Inflammasomes are intracellular multi‐protein complexes that act as key signalling hubs of the innate immune system. They respond to cellular stress and trauma by promoting activation of caspase‐1, a protease that induces a pro‐inflammatory cell death mode termed pyroptosis along with the maturation and secretion of the pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18. Here, we will briefly introduce inflammasome biology with a focus on the dual roles of inflammasome‐produced cytokines in cancer development. Despite emerging insight that inflammasomes may promote and suppress cancer development according to the tumour stage and the tumour microenvironment, much remains to be uncovered. Further exploration of inflammasome biology in tumorigenesis should enable the development of novel immunotherapies for cancer patients.

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Section: Introductionmentioning

confidence: 68%

The emerging roles of inflammasome‐dependent cytokines in cancer development

Gorp

Lamkanfi

2019

EMBO Reports

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“…NF-kB signaling is known to activate the NLRP3 inflammasome which generates IL-18 and IL-1B. 53 These ligands stimulate cells of the microenvironment, such as MDSCs 54 , to ultimately produce ligands such as S100A8, S100A9, TNF, and IL-1B, all of which stimulate receptor-mediated NF-kB signaling and thus complete a circuit. 51,53,55–58 The genes of this circuit belong to Pr-134, suggesting that NF-kB signaling is a driver of microenvironment-induced resistance.…”

Section: Discussionmentioning

confidence: 99%

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Wall

Turkarslan

et al. 2020

Preprint

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38Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients 39 ultimately relapse and many become refractory to their previous therapies. Although many 40 therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM 41 biology across patients impacts the likelihood of success for existing therapies and those in the 42 pipeline. Therefore, we not only need the ability to predict which patients are at high risk for 43 disease progression, but also a means to understand the mechanisms underlying their risk. We 44 hypothesized that knowledge of the biological networks that give rise to MM, specifically the 45 transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene 46 regulation, would enable improved predictions of disease progression and actionable insights for 47 treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the 48 generation of a MM TRN that links chromosomal abnormalities and somatic mutations to 49 downstream effects on gene expression via perturbation of transcriptional regulators. We find that 50 141 genetic programs underlie the disease and that the activity profile of these programs fall into 51 one of 25 distinct transcriptional states. These transcriptional signatures prove to be more 52 predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including 53 the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-54 specific vulnerabilities to interventions with existing drugs and motivate the development of new 55 targeted therapies that appear especially promising for relapsed refractory MM. 56 57 Introduction 58 59 Multiple Myeloma (MM) is a cancer of malignant plasma cells in the bone marrow (BM) that has 60 a prevalence of approximately 86,000 new cases per year. 1 Several clinical subtypes of MM have 61 been established on the basis of characteristic cytogenetic features, including various 62 translocations, gain or loss of chromosomal arms, deletion of specific chromosomes, and 63 hyperdiploidy. 2-4 Accordingly, MM is a complex disease of great heterogeneity that exhibits64 subtype-specific drivers of progression. 5,6 Efforts to better characterize the biology and 65 therapeutic vulnerabilities of MM have increased exponentially in recent years, as can be seen 66 from the number of research articles, clinical trials, and public availability of matched genomic, 67 transcriptomic, and patient data. However, the myriad combinations of chromosomal aberrations 68 and somatic mutations, coupled with the complex dependence of MM progression on the BM 69 microenvironment, have precluded a mechanistic understanding of the disease on a patient-70 specific level. 72The 5-year survival rate of MM is approximately 50% 7 , which is nearly double what it was in the 73 late 1980s. 8 The reason for the improved outcomes is a series of therapeutic advances that 74 include the introduction of autologous stem cell t...

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“…89 MM cancer cells are dependent on bone marrow microenvironmental factors for their survival, growth, and dissemination, and knockout mouse models are often used as tools to investigate the contribution of host derived factors on myeloma disease course. [95][96][97][98] Some of these approaches utilize single gene knockouts on a RAG2 −/− background to avoid the complication of any B-nor T-cell mediated tumor cell rejection 96,97 but others retain a fully functional adaptive immune system. Given the caveats outlined in this study, it is important for genetic knockout experiments to be complemented by molecular interference/inhibition of protein function wherever possible.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the role of Samsn1 loss in multiple myeloma development

et al. 2020

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The protein SAMSN1 was recently identified as a putative tumor suppressor in multiple myeloma, with re‐expression of Samsn1 in the 5TGM1/KaLwRij murine model of myeloma leading to a near complete abrogation of intramedullary tumor growth. Here, we sought to clarify the mechanism underlying this finding. Intratibial administration of 5TGM1 myeloma cells into KaLwRij mice revealed that Samsn1 had no effect on primary tumor growth, but that its expression significantly inhibited the metastasis of these primary tumors. Notably, neither in vitro nor in vivo migration was affected by Samsn1 expression. Both knocking‐out SAMSN1 in the RPMI‐8226 and JJN3 human myeloma cell lines, and retrovirally expressing SAMSN1 in the LP‐1 and OPM2 human myeloma cell lines had no effect on either cell proliferation or migration in vitro. Altering SAMSN1 expression in these human myeloma cells did not affect the capacity of the cells to establish either primary or metastatic intramedullary tumors when administered intratibially into immune deficient NSG mice. Unexpectedly, the tumor suppressive and anti‐metastatic activity of Samsn1 in 5TGM1 cells were not evidenced following cell administration either intratibially or intravenously to NSG mice. Crucially, the growth of Samsn1‐expressing 5TGM1 cells was limited in C57BL/6/Samsn1−/− mice but not in C57BL/6 Samsn1+/+ mice. We conclude that the reported potent in vivo tumor suppressor activity of Samsn1 can be attributed, in large part, to graft‐rejection from Samsn1−/− recipient mice. This has broad implications for the design and interpretation of experiments that utilize cancer cells and knockout mice that are mismatched for expression of specific proteins.

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Dysregulated IL-18 Is a Key Driver of Immunosuppression and a Possible Therapeutic Target in the Multiple Myeloma Microenvironment

Cited by 173 publications

References 54 publications

The emerging roles of inflammasome‐dependent cytokines in cancer development

The emerging roles of inflammasome‐dependent cytokines in cancer development

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Characterization of the role of Samsn1 loss in multiple myeloma development

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