CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Intratumoral IL-33 + CD4 + FoxP3 + regulatory T cell infiltration determines poor clinical outcomes and intensive immunoevasive contexture in patients with pancreatic cancer after surgical resection: a cohort study.
Intratumoral IL-33 + CD4 + FoxP3 + regulatory T cell infiltration determines poor clinical outcomes and intensive immunoevasive contexture in patients with pancreatic cancer after surgical resection: a cohort study.
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我们的研究结果确定了 IL-33 + Tregs 是 Tregs 的一种新亚型，在 PDAC 的生存风险分层和治疗反应预测中具有强大的预后价值。IL-33 + Tregs 表现出更明显的免疫抑制能力，损害 CD8 + T 细胞功能。随着进一步研究，IL-33 + Tregs 可能代表 PDAC 的一个有前景的免疫治疗靶点。
白细胞介素-33（IL-33）是IL-1细胞因子家族的成员，在内皮细胞和成纤维细胞等屏障细胞中呈组成性表达。虽然此前已有报道指出调节性T细胞（Tregs）中IL-33的表达，但其在胰腺导管腺癌（PDAC）中的临床意义仍不明确。本研究旨在探讨IL-33 + Tregs在PDAC中的临床相关性及生物学作用。
通过免疫组化评估了我院215例患者中IL-33 + Tregs的浸润情况。分析了IL-33 + Tregs与临床特征之间的相关性。此外，还检查了细胞毒性T细胞的功能状态与IL-33 + Treg浸润的关系。进一步通过计算机模拟和体外实验评估了IL-33 + Tregs对肿瘤微环境（TME）的影响。
在PDAC组织中证实了IL-33 + Tregs的浸润，其丰度与微血管侵犯、神经周围侵犯和血清CA19-9水平升高呈正相关。与浸润水平较低的患者相比，肿瘤浸润IL-33 + Tregs较高的患者表现出更差的总生存期（OS）和无复发生存期（RFS）。多因素分析证实IL-33 + Tregs是OS和RFS的独立预后因素，与肿瘤分化联合时可改善生存预测。亚组分析表明，血清CA19-9在高IL-33 + Treg浸润患者中不是有用的风险分层工具，这些患者从辅助化疗中获得的生存获益有限。此外，IL-33 + Treg浸润增加与更明显的免疫抑制性TME相关，其特征是细胞毒性表型减少和CD8 + T细胞上耗竭标志物上调。
Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is constitutively expressed in barrier cells such as endothelial cells and fibroblasts. While the expression of IL-33 in regulatory T cells (Tregs) has been previously reported, its clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study aims to investigate the clinical relevance and biological role of IL-33 + Tregs in PDAC.
Infiltration of IL-33 + Tregs was assessed by immunohistochemistry in 215 patients from our institute. The correlation between IL-33 + Tregs and clinical characteristics was analyzed. Additionally, the functional status of cytotoxic T cells in relation to IL-33 + Treg infiltration was examined. The impact of IL-33 + Tregs on the tumor microenvironment (TME) was further evaluated both in silico and in vitro .
IL-33 + Tregs infiltration was confirmed in PDAC tissues, and its abundance was positively associated with microvascular invasion, perineural invasion, and elevated serum CA19-9 levels. Patients with higher tumor-infiltrating IL-33 + Tregs demonstrated poorer overall survival (OS) and recurrence-free survival (RFS) compared to those with lower infiltration levels. Multivariate analysis confirmed IL-33 + Tregs as an independent prognostic factor for both OS and RFS, with improved survival prediction when combined with tumor differentiation. Subgroup analyses indicated that serum CA19-9 was not a useful risk stratification tool in patients with high IL-33 + Treg infiltration, and these patients showed limited survival benefit from adjuvant chemotherapy. Furthermore, increased IL-33 + Treg infiltration was associated with more pronounced immunosuppressive TME, marked by a reduction in cytotoxic phenotypes and an upregulation of exhausted markers on CD8 + T cells.
Our findings identify IL-33 + Tregs as a novel subtype of Tregs, with strong prognostic value for survival risk stratification and therapeutic response prediction in PDAC. IL-33 + Tregs exhibit more pronounced immunosuppressive capabilities, impairing CD8 + T cell function. With further investigation, IL-33 + Tregs may represent a promising immunotherapeutic target for PDAC.
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