Foxp3-expressing regulatory T (Treg) cells represent the most highly immunosuppressive cell in the tumor microenvironment (TME) that halts effective anti-tumor immunity. Osteopontin (Opn), an extracellular matrix (ECM) glycophosphoprotein, plays key roles in many types of immune-related diseases and is associated with cancer aggressiveness when expressed by tumor cells. However, its role in Foxp3Treg heterogeneity, function, and stability in the TME is poorly defined. We generated mice with a Foxp3-specific deletion of Opn and assessed the ability of Opn-deficient Tregs to suppress inflammation. As these mice aged, they developed a scurfy-like syndrome characterized by aberrant and excessive activation of effector T cells. We evaluated and further confirmed the reduced suppressive capacity of Opn-deficient Tregs in an in vivo suppression assay of colitis. We also found that mice with Opn-deficient Foxp3+Tregs have enhanced anti-tumor immunity and reduced tumor burden, associated with an unstable Treg phenotype, paralleled by reduced Foxp3 expression in tumor-infiltrating lymphocytes. Finally, we observed reduced Foxp3 and Helios expression in Opn-deficient Tregs compared to wild-type controls after in vitro activation. Our findings indicate that targeting Opn in Tregs reveals vigorous and effective ways of promoting Treg instability and dysfunction in the TME, facilitating anti-tumor immunity.
表达Foxp3的调节性T细胞（Treg）是肿瘤微环境（TME）中免疫抑制能力最强的细胞，可阻碍有效的抗肿瘤免疫。骨桥蛋白（Opn）作为一种细胞外基质糖磷蛋白，在多种免疫相关疾病中发挥关键作用，当其在肿瘤细胞中表达时与癌症侵袭性相关。然而，Opn在TME中对Foxp3+Treg细胞的异质性、功能及稳定性的作用尚不明确。本研究构建了Foxp3特异性敲除Opn的小鼠，并评估了Opn缺陷型Treg抑制炎症的能力。随着小鼠年龄增长，它们出现了类似scurfy综合征的表型，其特征是效应T细胞的异常过度活化。通过结肠炎体内抑制实验，我们评估并进一步证实了Opn缺陷型Treg的抑制能力下降。同时发现，Opn缺陷的Foxp3+Treg小鼠表现出增强的抗肿瘤免疫和降低的肿瘤负荷，这与Treg表型不稳定相关，并伴随肿瘤浸润淋巴细胞中Foxp3表达的降低。最后，我们观察到体外活化后，与野生型对照组相比，Opn缺陷型Treg中Foxp3和Helios的表达均下降。我们的研究结果表明，靶向Treg中的Opn为促进TME中Treg不稳定和功能障碍、增强抗肿瘤免疫提供了强效且可行的策略。
肿瘤(癌症)患者之家