Effect of CDK5 knockdown on the cytotoxic potential of T cell subpopulations

Malignant tumors of the central nervous system (CNS) are poorly immunogenic, thus limiting the effectiveness of therapies and contributes to a dismal prognosis for patients with these malignancies. Therefore, the development of new approaches to treatment of these diseases is becoming increasingly important. Atypical cyclin-dependent kinase 5 ( CDK5 ) is involved in tumor progression and metastasis, as well as in developing immune escape by modifying the expression of MHC-I molecules and immune checkpoints, being 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 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 murine model upon functional status of cytotoxic T lymphocytes in the microenvironment of CNS cancers in order to compare the experimental results with clinical data of patients with CNS tumors. The objectives of our study were as follows: to analyze the expression profile of genes associated with the T cell response using scRNA-seq in a murine model of the disease with CDK5 knockdown; to validate changes in infiltration and effector molecule expression using immunohistochemistry (IHC) technique; bioinformatic evaluation of correlations between CDK5 expression levels and cytotoxic genes in cohorts of patients with brain metastases and primary glioblastoma using bulk- and scRNA-seq; to assess 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 results of this analysis may provide a more accurate prognosis of patient survival based on the level of expression of CDK5 and effector molecules. Further studies are required to elucidate the conditions and characteristics that mediate the immunomodulatory effect of CDK5 .