INVESTIGATING THE INFLUENCE OF STAT1 PHOSPHORYLATION AT SER727 ON CD8+ T-CELL INFILTRATION IN CENTRAL NERVOUS SYSTEM TUMORS

Phosphorylation of the STAT1 protein at serine 727 (pSTAT1_S727) is a key post-translational modification whose function in the anti-tumor immune response within malignant central nervous system (CNS) tumors remains insufficiently understood. This study aimed to determine the role of pSTAT1_S727 in immune modulation in the most aggressive brain tumor – glioblastoma. The results demonstrated that STAT1_S727 phosphorylation is closely associated with the activation of the anti-tumor immune system. A positive correlation was found between pSTAT1_S727 levels and the expression of genes encoding components of the major histocompatibility complex class I (MHC-I), as well as other genes involved in tumor antigen presentation. This indicates that pSTAT1_S727 plays an important role in enhancing the antigen-presenting capacity of glioblastoma cells, a critical step for tumor recognition by the immune system. Furthermore, high levels of pSTAT1_S727 were statistically significantly correlated with increased intensity of tumor infiltration by cytotoxic CD8+ T-cells. These observations were consistently confirmed both in data from glioblastoma patients and in experimental mouse models, underscoring the significance of the identified relationship. Thus, STAT1_S727 phosphorylation has been identified as an important molecular factor promoting the initiation of immune recognition of glioblastoma by enhancing antigen presentation and recruiting effector T-cells. However, despite this pro-inflammatory role, survival analysis of patients did not reveal an association between high pSTAT1_S727 levels and improved overall survival. This lack of clinical benefit is likely explained by the profoundly immunosuppressive environment characteristic of glioblastoma, where infiltrating T-cells are often functionally exhausted, and the tumor actively employs immune evasion mechanisms. Consequently, while activation of the pSTAT1_S727 signaling pathway is necessary for initiating an immune response, it is insufficient on its own to overcome immunosuppression and achieve a significant therapeutic effect. The obtained data highlight the need for combined strategies that simultaneously enhance the initiation of the immune response (e.g., through STAT1 activation) and block mechanisms of T-cell exhaustion within the tumor microenvironment.

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