ANALYSIS OF THE EFFECT OF Cdk5 KNOCKDOWN ON THE CYTOTOXIC POTENTIAL OF T-CELL SUBPOPULATIONS

Malignant tumors of the central nervous system (CNS) are poorly immunogenic, which limits the effectiveness of therapies and contributes to an unfavorable prognosis for patients with this pathology. Therefore, the development of new approaches to treating this group of diseases is becoming increasingly important. Atypical cyclin-dependent kinase 5 (CDK5) is involved in tumor progression and metastasis, as well as in the formation of immune escape by modifying the expression of MHC-I molecules and immune checkpoints, is an important candidate for regulating the molecular mechanisms of tumor growth. However, the influence of CDK5 on the functional state of T-cell subsets and the expression of key cytotoxic effectors in the microenvironment of primary and metastatic CNS cancers remains poorly understood. The aim of this study was to evaluate the effect of Cdk5 gene knockdown in tumor cells of mouse model on the functional status of cytotoxic T lymphocytes in the microenvironment of CNS cancers for comparation of experimental results with clinical data of patients diagnosed with CNS tumors. The objectives were to: (1) analyze the expression profile of genes associated with the T cell response using scRNA-seq in a mouse model of Cdk5 knockdown disease; (2) validate changes in infiltration and effector molecule expression using immunohistochemistry (IHC); (3) bioinformatically evaluate correlations between CDK5 expression levels and cytotoxic genes in cohorts of patients with brain metastases and primary glioblastoma using bulk- and scRNA-seq; and (4) analyze the impact of effector molecule expression on overall patient survival. Our results indicate that CDK5 expression levels influence the transcriptional activity of genes encoding key T cell effector molecules such as perforin or granzymes. The following of the analysis may be the possibility of formulating more accurate prognoses of patient survival based on the level of expression of CDK5 and effector molecules. Further studies are needed to elucidate the conditions and characteristics that mediate the immunomodulatory effect of CDK5.

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