IL-23 stabilizes an effector Treg cell program in the tumor microenvironment

Wertheimer, Tobias; Zwicky, Pascale; Rindlisbacher, Lukas; Sparano, Colin; Vermeer, Marijne; de Melo, Bruno Marcel Silva; Haftmann, Claudia; Rückert, Tamina; Sethi, Aakriti; Schärli, Stefanie; Huber, Anna; Ingelfinger, Florian; Xu, Caroline; Kim, Daehong; Häne, Philipp; Fonseca da Silva, André; Muschaweckh, Andreas; Nunez, Nicolas; Krishnarajah, Sinduya; Köhler, Natalie; Zeiser, Robert; Oukka, Mohamed; Korn, Thomas; Tugues, Sonia; Becher, Burkhard

doi:10.1038/s41590-024-01755-7

Cited by 5 publications

(1 citation statement)

References 72 publications

(119 reference statements)

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“… 39 In a recent research, Tobias Wertheimer et al found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. 40 Consistent with previous studies, in this work, we found that IL-23, as a severe-irAEs-associated gene, was mainly transcribed by monocytes in human peripheral blood based on scRNA-seq analysis.…”

Section: Discussionsupporting

confidence: 92%

Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy

Ju,

Zhang,

Deng

et al. 2024

J Immunother Cancer

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BackgroundImmune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood.MethodsThe pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2−/−Il2rg−/−mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly.ResultsHere we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4+Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features—IL-23 and CD4+Tems—that may have predictive potential for severe irAEs and ICIs response.ConclusionsOur study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.

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Section: Discussionsupporting

confidence: 92%

Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy

Ju,

Zhang,

Deng

et al. 2024

J Immunother Cancer

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Edodes Cultured Extract Regulates Immune Stress During Puberty and Modulates MicroRNAs Involved in Mammary Gland Development and Breast Cancer Suppression

Yasavoli‐Sharahi,

Shahbazi,

Alsadi

et al. 2024

Cancer Medicine

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BackgroundImmune stressors, such as lipopolysaccharides (LPS), profoundly affect microbiota balance, leading to gut dysbiosis. This imbalance disrupts the metabolic phenotype and structural integrity of the gut, increasing intestinal permeability. During puberty, a critical surge in estrogen levels is crucial for mammary gland development. However, inflammation originating from the gut in this period may interfere with this development, potentially heightening breast cancer risk later. The long‐term effects of pubertal inflammation on mammary development and breast cancer risk are underexplored. Such episodes can dysregulate cytokine levels and microRNA expression, altering mammary cell gene expression, and predisposing them to tumorigenesis.MethodsThis study hypothesizes that prebiotics, specifically Lentinula edodes Cultured Extract (AHCC), can counteract LPS's adverse effects. Using BALB/c mice, an acute LPS dose was administered at puberty, and breast cancer predisposition was assessed at 13 weeks. Cytokine and tumor‐related microRNA levels, tumor development, and cancer stem cells were explored through immunoassays and qRT‐PCR.ResultsResults show that LPS induces lasting effects on cytokine and microRNA expression in mammary glands and tumors. AHCC modulates cytokine expression, including IL‐1β, IL‐17A/F, and IL‐23, and mitigates LPS‐induced IL‐6 in mammary glands. It also regulates microRNA expression linked to tumor progression and suppression, particularly counteracting the upregulation of oncogenic miR‐21, miR‐92, and miR‐155. Although AHCC slightly alters some tumor‐suppressive microRNAs, these changes are modest, highlighting a complex regulatory role that warrants further study.ConclusionThese findings underscore the potential of dietary interventions like AHCC to mitigate pubertal LPS‐induced inflammation on mammary gland development and tumor formation, suggesting a preventive strategy against breast cancer.

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A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron

Sharma,

Kim

et al. 2024

Nat Immunol

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IL-23 stabilizes an effector Treg cell program in the tumor microenvironment

Cited by 5 publications

References 72 publications

Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy

Prophylactic IL-23 blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy

Edodes Cultured Extract Regulates Immune Stress During Puberty and Modulates MicroRNAs Involved in Mammary Gland Development and Breast Cancer Suppression

A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron

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