Evidence for IL-35 Expression in Diffuse Large B-Cell Lymphoma and Impact on the Patient's Prognosis

Larousserie, Frédérique; Kebe, Diakho; Huynh, Tony; Audebourg, Anne; Tamburini, Jérôme; Terris, Benoı̂t; Devergne, Odile

doi:10.3389/fonc.2019.00563

Cited by 21 publications

(18 citation statements)

References 43 publications

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“…When the IL-12Rβ1 subunit is combined with the Ebi3 subunit, it becomes an immunosuppressive unit activated by IL35 35 . IL-35, a pro-tumor member of the IL12 cytokine family, is overexpressed in DLBCL 36 and suppresses naive T-cell activation 37 . In a phase II clinical trial for non-Hodgkin's Lymphoma and Hodgkin's Lymphoma, IL12 administration increased circulating CD8+ T-cell presence but had no effect on CD4+ T-cell presence 38 .…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma

et al. 2021

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The clinical risk stratification of diffuse large B-cell lymphoma (DLBCL) relies on the International Prognostic Index (IPI) for the identification of high-risk disease. Recent studies suggest that the immune microenvironment plays a role in treatment response prediction and survival in DLBCL. This study developed a risk prediction model and evaluated the model’s biological implications in association with the estimated profiles of immune infiltration. Gene-expression profiling of 718 patients with DLBCL was done, for which RNA sequencing data and clinical covariates were obtained from Reddy et al. (2017). Using unsupervised and supervised machine learning methods to identify survival-associated gene signatures, a multivariable model of survival was constructed. Tumor-infiltrating immune cell compositions were enumerated using CIBERSORT deconvolution analysis. A four gene-signature-based score was developed that separated patients into high- and low-risk groups. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The gene signatures were successfully validated with the deconvolution output. Correlating the deconvolution findings with the gene signatures and risk score, CD8+ T-cells and naïve CD4+ T-cells were associated with favorable prognosis. By analyzing the gene-expression data with a systematic approach, a risk prediction model that outperforms the existing risk assessment methods was developed and validated.

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Section: Discussionmentioning

confidence: 99%

Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma

et al. 2021

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“…Similar studies reported elevated levels of circulating IL-35 in breast cancer patients, which positively correlated with the expression of Ki67, p53 and EGFR on breast cancer cells [ 192 ]. Furthermore, high levels of IL-35 were shown to be associated with the poor survival of diffuse-large B-cell lymphoma (DLBCL) patients treated with chemotherapy [ 193 ]. Additionally, increased levels of IL-35 were observed in the bone marrow of acute myeloid leukemia (AML) patients and correlated positively with clinical stages [ 194 ].…”

Section: Introduction Il-12 Family Cytokines: Composition Signalmentioning

confidence: 99%

IL-12 Family Cytokines in Cancer and Immunotherapy

Mirlekar

Pylayeva-Gupta

2021

Cancers

184

102

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The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.

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“…This suggests that in wild-type mice, the EBI3 subunit might preferentially dimerize with the IL-12p35 subunit to form the anti-inflammatory cytokine IL-35. Although attempts were made to clarify the binding partner of EBI3 by co-immunoprecipitation, this proved unfeasible owing to the near identical sizes of IL-12 family members and the known lack of reliable commercial antibodies [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic histone modulation contributes to improvements in inflammatory bowel disease via EBI3

Wetzel¹,

Scholtka²,

Gerecke³

et al. 2020

Cell. Mol. Life Sci.

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Ulcerative colitis (UC) is characterized by relapsing-remitting inflammatory episodes paralleled by varying cytokine levels, suggesting that switching epigenetic processes might be involved. However, the epigenetic impact on cytokine levels in colitis is mostly unexplored. The heterodimeric interleukin (IL)-12 cytokine family have various functions in both pro-and antiinflammatory processes. The family member IL-35 (EBI3/IL-12p35) was recently reported to play an anti-inflammatory role in UC. Therefore, we aimed to investigate a possible epigenetic regulation of the IL-35 subunits in vitro and in vivo, and to examine the epigenetic targeting of EBI3 expression as a therapeutic option for UC. Exposure to either the pro-inflammatory TNFα or to histone deacetylase inhibitors (HDACi) significantly increased EBI3 expression in Human Colon Epithelial Cells (HCEC) generated from healthy tissue. When applied in combination, a drastic upregulation of EBI3 expression occurred, suggesting a synergistic mechanism. Consequently, IL-35 was increased as well. In vivo, the intestines of HDACi-treated wild-type mice exhibited reduced pathological signs of colitis compared to non-treated colitic mice. However, the improvement by HDACi treatment was completely lost in Ebi3-deficient mice (Ebi3 −/−). In fact, HDACi appeared to exacerbate the disease phenotype in Ebi3 −/−. In conclusion, our results reveal that under inflammatory conditions, EBI3 is upregulated by the epigenetic mechanism of histone acetylation. The in vivo data show that the deficiency of EBI3 plays a key role in colitis manifestation. Concordantly, our data suggest that conditions promoting histone acetylation, such as upon HDACi application, improve colitis by a mechanism involving the local formation of the anti-inflammatory cytokine IL-35.

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Evidence for IL-35 Expression in Diffuse Large B-Cell Lymphoma and Impact on the Patient's Prognosis

Cited by 21 publications

References 43 publications

Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma

Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma

IL-12 Family Cytokines in Cancer and Immunotherapy

Epigenetic histone modulation contributes to improvements in inflammatory bowel disease via EBI3

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