ArticleJournal for immunotherapy of cancer2024
Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy.
Article in Journal for immunotherapy of cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- γδ T cells and cancer.The Journal of clinical investigation · 2026Review
- Peripheral blood mRNA expression of IL37, IL1F10, and C17orf99 genes is altered in patients with B-acute lymphoblastic leukemia: a case-control study.Molecular biology reports · 2026Article
- A Literature Review of Interleukins in the Development and Treatment of Breast Cancer.International journal of molecular sciences · 2026Review
- Mast Cells Accumulate in the Stroma of Breast Adenocarcinoma and Secrete Pro-Inflammatory Cytokines and Tumor-Damaging Mediators: Could IL-37 and IL-38 Play an Anti-Tumor Role?International journal of molecular sciences · 2026Review
- Article
- The regulatory role of IL-37 and IL-38 in CAR-T associated cytokine release syndrome in multiple myeloma.Frontiers in immunology · 2026Review
- Review
- The distinct roles of IL-37 and IL-38 in non-small cell lung carcinoma and their clinical implications.Frontiers in immunology · 2025Review
- Leucine-rich repeat neuronal 1 as a prognostic indicator and functional modulator in breast cancer.Frontiers in oncology · 2025Article
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe interleukin (IL)-1-family receptor antagonist IL-38 has emerged as a negative regulator of auto-inflammation. Given the intricate interplay between antitumor immunity and auto-inflammation, we hypothesized that blocking IL-38 may enhance tumor immune control.
methodsOur hypothesis was tested in the transgenic polyoma virus middle T oncoprotein mammary carcinoma model that is suitable for identifying strong immunomodulators. To investigate the effect of acute IL-38 blockade, we used a neutralizing antibody, alone or in combination with chemotherapy. Immune cell composition and location in tumors were determined by flow cytometry and immunohistochemistry, respectively. The role of γδ T cells was studied using an antibody blocking γδ T-cell receptor signaling. Whole transcriptome RNA sequencing and RNA expression analysis were employed to determine mechanisms downstream of IL-38 neutralization. Additionally, in vitro assays with γδ T cells, CD8+ T cells and cDC1, followed by in vivo CD8+ T cell depletion, were performed to study the underlying mechanistic pathways.
resultsBoth, genetic ablation of IL-38 and neutralization with the antibody, reduced tumorigenesis, and IL-38 blockade improved chemotherapy efficacy. This was accompanied by an augmented lymphocyte infiltrate dominated by γδ T cells and CD8+ T cells, and signaling through the γδ-T-cell receptor was required for CD8+ T cell infiltration. Rather than directly interacting with CD8+ T cells, γδ T cells recruited conventional dendritic cells (cDC1) into tumors via the chemokine Xcl1. cDC1 in turn activated CD8+ T cells via the Notch pathway. Moreover, IL-38 negatively correlated with cDC1, XCL1-producing γδ T cells, T-cell infiltrates and survival in patients with mammary carcinoma.
conclusionsThese data suggest that interfering with IL-38 improves antitumor immunity even in immunologically cold tumors.
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