白细胞介素 (IL)-1 家族受体拮抗剂 IL-38 已成为自身炎症的负调节剂。鉴于抗肿瘤免疫和自身炎症之间复杂的相互作用，我们假设阻断 IL-38 可能会增强肿瘤免疫控制。我们的假设在适合鉴定强免疫调节剂的转基因多瘤病毒中 T 癌蛋白乳腺癌模型中得到了检验。为了研究急性 IL-38 阻断的效果，我们单独使用中和抗体或与化疗联合使用。分别通过流式细胞术和免疫组织化学测定肿瘤中的免疫细胞组成和位置。使用阻断 γδ T 细胞受体信号传导的抗体研究了 γδ T 细胞的作用。采用全转录组 RNA 测序和 RNA 表达分析来确定 IL-38 中和的下游机制。此外，还进行了 γδ T 细胞、CD8 T 细胞和 cDC1 的体外测定，然后进行体内 CD8 T 细胞耗竭，以研究潜在的机制途径。IL-38 的基因消除和抗体的中和都减少了肿瘤发生和 IL-38 阻断可提高化疗疗效。伴随着以 γδ T 细胞和 CD8 T 细胞为主的淋巴细胞浸润增加，并且 CD8 T 细胞浸润需要通过 γδ-T 细胞受体的信号传导。 γδ T 细胞不是直接与 CD8 T 细胞相互作用，而是通过趋化因子 Xcl1 将传统树突状细胞 (cDC1) 招募到肿瘤中。 cDC1 反过来通过 Notch 途径激活 CD8 T 细胞。此外，IL-38 与乳腺癌患者中产生 cDC1、XCL1 的 γδ T 细胞、T 细胞浸润和生存呈负相关。这些数据表明，即使在免疫冷肿瘤中，干扰 IL-38 也能改善抗肿瘤免疫力。© 作者（ s)（或其雇主）2024。CC BY 允许重复使用。英国医学杂志出版。

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.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.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.These data suggest that interfering with IL-38 improves antitumor immunity even in immunologically cold tumors.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.