Dataset Information

Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy.

ABSTRACT:

Background

The 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.

Methods

Our 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.

Results

Both, 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.

Conclusions

These data suggest that interfering with IL-38 improves antitumor immunity even in immunologically cold tumors.

SUBMITTER: da Silva P

PROVIDER: S-EPMC11367332 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Publications

Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy.

da Silva Priscila P Mora Javier J You Xin X Wiechmann Svenja S Putyrski Mateusz M Garcia-Pardo Javier J Kannt Aimo A Ernst Andreas A Bruene Bernhard B Weigert Andreas A

Journal for immunotherapy of cancer 20240828 8

<h4>Background</h4>The 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.<h4>Methods</h4>Our 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 ...[more]

PMID: 39209451

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Project description:Immunomodulatory agents that induce antitumor immunity have great potential for treatment of cancer. We have previously shown that interleukin (IL)-31, a proinflammatory cytokine from the IL-6 family, acts as an antiangiogenic agent. Here, we characterize the immunomodulatory effect of IL-31 in breast cancer. In vivo breast carcinoma models including EMT6 and PyMT cell lines were used to analyze the effect of IL-31 on the composition of various immune cells in the tumor microenvironment using high-throughput flow cytometry. In vitro studies using isolated cytotoxic T cells, CD4+ T cells, myeloid-derived suppressor cells (MDSCs) and macrophages were carried out to study IL-31 immunological activity. The generation of recombinant IL-31 bound to IgG backbone was used to test IL-31 therapeutic activity. The growth rate of IL-31-expressing breast carcinomas is decreased in comparison with control tumors due, in part, to antitumor immunomodulation. Specifically, cytotoxic T cell activity is increased, whereas the levels of CD4+ T cells, MDSCs, and tumor-associated macrophages are decreased in IL-31-expressing tumors. These cellular changes are accompanied by a cytokine profile associated with antitumor immunity. In vitro, IL-31 directly inhibits CD4+ Th0 cell proliferation, and the expression of Th2 canonical factors GATA3 and IL-4. It also promotes CD8+ T cell activation through inhibition of MDSC activity and motility. Clinically, in agreement with the mouse data, alterations in immune cell composition in human breast cancer biopsies were found to correlate with high expression of IL-31 receptor A (IL-31Ra) . Furthermore, high coexpression of IL-31Ra, IL-2 and IL-4 in tumors correlates with increased survival. Lastly, to study the therapeutic potential of IL-31, a recombinant murine IL-31 molecule was fused to IgG via a linker region (IL-31-L-IgG). This IL-31-L-IgG therapy demonstrates antitumor therapeutic activity in a murine breast carcinoma model. Our findings demonstrate that IL-31 induces antitumor immunity, highlighting its potential utility as a therapeutic immunomodulatory agent.

Dataset Information

Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy.

Background

Methods

Results

Conclusions

Publications

Neutralizing IL-38 activates γδ T cell-dependent antitumor immunity and sensitizes for chemotherapy.

Similar Datasets

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