1. Osteopontin Regulates Treg Cell Stability and Function with Implications for Anti-Tumor Immunity and Autoimmunity.
- Author
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Vakrakou, Aigli G., Kourepini, Evangelia, Skordos, Ioannis, Nieto, Natalia, Panoutsakopoulou, Vily, and Paschalidis, Nikolaos
- Subjects
TUMOR treatment ,PROTEIN metabolism ,T cells ,RESEARCH funding ,KRUSKAL-Wallis Test ,CANCER patients ,MANN Whitney U Test ,DESCRIPTIVE statistics ,MICE ,GENE expression ,ANIMAL experimentation ,ONE-way analysis of variance ,TUMORS ,INFLAMMATION ,DATA analysis software ,IMMUNITY ,PHENOTYPES - Abstract
Simple Summary: T regulatory cells are specialized lymphocytes that prevent excessive immune responses, yet they can suppress beneficial anti-tumor immunity when infiltrating malignant tumors. Osteopontin, a versatile protein produced by various cells, including T lymphocytes, influences both inflammation-related diseases and cancer immunity. Its role in T regulatory cells, however, remains less explored. Our study examined the impact of osteopontin deficiency on T regulatory cells. We generated mice lacking osteopontin in these cells and observed impaired immune suppression capabilities, which resulted in increased tumor-fighting activity against melanoma. These findings emphasize osteopontin's crucial role in T regulatory cell stability and functionality within the tumor microenvironment, providing valuable insights for developing new immunotherapeutic strategies. 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. [ABSTRACT FROM AUTHOR]- Published
- 2024
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