| First Author | da Silva P | Year | 2024 |
| Journal | J Immunother Cancer | Volume | 12 |
| Issue | 8 | PubMed ID | 39209451 |
| Mgi Jnum | J:354202 | Mgi Id | MGI:7731025 |
| Doi | 10.1136/jitc-2023-008641 | Citation | da Silva P, et al. (2024) Neutralizing IL-38 activates gammadelta T cell-dependent antitumor immunity and sensitizes for chemotherapy. J Immunother Cancer 12(8) |
| abstractText | 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 gammadelta T cells was studied using an antibody blocking gammadelta 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 gammadelta 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 gammadelta T cells and CD8+ T cells, and signaling through the gammadelta-T-cell receptor was required for CD8+ T cell infiltration. Rather than directly interacting with CD8+ T cells, gammadelta 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 gammadelta 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. |
