The related mechanism by which CDK1, CDK2, and CDK5 in tumor cells regulate the tumor immune microenvironment. (IMAGE)
Caption
(A) CDK1 is highly expressed in lung adenocarcinoma tumor tissue, and CDK1 expression is positively correlated with CXCL8 expression in macrophages, forming an immunosuppressive microenvironment through macrophages and thereby promoting tumor progression. Inhibition of CDK1 down-regulates the transcriptional activation of CXCL8 and reverses the macrophage-induced immunosuppressive microenvironment, thereby inhibiting tumor proliferation. (B) The level of the cyclin E/CDK2 complex is increased in basal-like/TNBC cells, and SNS-032 has a potent inhibitory effect on CDK2. SNS-032 treatment can generate a large amount of cell debris by killing tumor cells, thus promoting T lymphocyte recruitment and activating the immune system’s antitumor surveillance arm. Further studies showed that SNS-032 could up-regulate the expression of PD-L1 in some surviving TNBC cells. The combination of SNS-032 with avelumab can enhance the cytotoxicity of NK cells, thereby triggering NK cell-mediated antibody-dependent cell-mediated cytotoxicity. (C) On the one hand, IFN-γ stimulation of medulloblastoma cells can stimulate IRF-1-driven PD-L1 transcription. On the other hand, IFN-γ stimulates p35 expression, thereby increasing CDK5 activity. CDK5 can reduce the abundance of the IRF2/IRF2BP2 inhibitor complex through the action of an unknown kinase, thereby relieving the inhibition of PD-L1 transcription. Specific knockout of the CDK5 gene down-regulated the expression of PD-L1 in tumor cells, increased the number of CD8+ T cells in the microenvironment, and decreased the number of Tregs.
Credit
Qingbo Zhu, Xiaoli Wei, Ziting Qu, Lili Lu, Yiyin Zhang, Hua Wang
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