CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer

Abstract

Background: The cyclin-dependent kinase 7 (CDK7) subunit of TFIIH regulates RNA polymerase-II-based transcription and promotes tumor progression. However, the mechanisms involved in CDK7-mediated immune evasion are unclear in non-small cell lung cancer (NSCLC). Methods: RNA silencing and pharmacologic inhibitors were used to evaluate the functions of CDK7/p38α/MYC/PD-L1 axis in cancer cell proliferation and antiPD-1 therapy resistance. Flow cytometry was performed to detect the status of the immune microenvironment after CDK7 inhibition and antiPD-1 therapy in vivo. CD8 depletion antibodies were used to assess the role of CD8 + T cells in combined CDK7 and PD-1 blockade. The associations among CDK7, p38α, MYC, PD-L1, infiltrating T cells, and survival outcomes were validated in two tissue microarrays and public transcriptomic data of NSCLC. Results: High CDK7 mRNA and protein levels were identified to be associated with poor prognosis in NSCLC. CDK7 silencing and CDK7 inhibitor THZ1 elicited apoptosis and suppressed tumor growth. Moreover, CDK7 ablation specifically suppressed p38α/MYC-associated genes, and THZ1 inhibited MYC transcriptional activity through downregulating p38α. CDK7 inhibition sensitized NSCLC to p38α inhibitor. Further, THZ1 suppressed PD-L1 expression by inhibiting MYC activity. THZ1 boosted antitumor immunity by recruiting infiltrating CD8 + T cells and synergized with antiPD-1 therapy. The CDK7/MYC/PD-L1 signature and infiltrating T cell status collectively stratified NSCLC patients into different risk groups. Conclusion: These data suggest that the combined CDK7 inhibitor THZ1 and antiPD-1 therapy can be an effective treatment in NSCLC.

CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B-Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism

“…More recently, several studies have reported that THZ1 suppresses cell growth and induces cell apoptosis of tumors by downregulating the c-MYC expression (13,20,43). A new study has revealed that THZ1 enhances anti-PD-1 therapy efficacy via the c-MYC-mediated signaling pathway in non-small cell lung cancer (44). Consistent with these findings, we uncovered that THZ1 considerably diminished the mRNA levels and protein expression of c-MYC in B-ALL cells.…”

Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer

“…Furthermore, chromatin immunoprecipitation (ChIP)-seq assay revealed that MYC binds to PD-L1 promoter [ 86 ], indicating that MYC directly regulates PD-L1 expression transcriptionally. Cyclin-dependent kinase 7 (CDK7)/MYC/PD-L1 signaling cascade have been demonstrated to enhance PD-L1 expression, and the CDK7 inhibitor, THZ1, downregulated PD-L1 expression by suppressing MYC activity in NSCLC [ 91 ]. MYC also critically mediated S100A9-induced PD-L1 expression [ 92 ].…”

Immunomodulation by targeted anticancer agents

“…Although a selective pharmacological inhibitor is still missing, deletion of Cdk8 in NK cells results in superior effector functions coupled to robust control of syngeneic melanomas, lymphomas, and leukemias (Witalisz-Siepracka et al, 2018). Pharmacological inhibition of CDK7 in lung cancer cells promotes genomic instability linked to the secretion of T-helper 1 (T H 1) cytokines such as tumor necrosis factor (TNF), chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL10, as well as PD-L1 downregulation as a consequence of mitogen-activated protein kinase 14 (MAPK14, best known as p38) and MYCN proto-oncogene, bHLH transcription factor (MYCN) repression (Wang et al, 2020b;Zhang et al, 2020a). Consistent with this notion, CDK7 inhibition in mice bearing syngeneic lung cancers promotes tumor infiltration by immune effector cells and can be successfully combined with ICIs targeting PD-1 (Wang et al, 2020b;Zhang et al, 2020a).…”

“…Pharmacological inhibition of CDK7 in lung cancer cells promotes genomic instability linked to the secretion of T-helper 1 (T H 1) cytokines such as tumor necrosis factor (TNF), chemokine (C-X-C motif) ligand 9 (CXCL9), and CXCL10, as well as PD-L1 downregulation as a consequence of mitogen-activated protein kinase 14 (MAPK14, best known as p38) and MYCN proto-oncogene, bHLH transcription factor (MYCN) repression (Wang et al, 2020b;Zhang et al, 2020a). Consistent with this notion, CDK7 inhibition in mice bearing syngeneic lung cancers promotes tumor infiltration by immune effector cells and can be successfully combined with ICIs targeting PD-1 (Wang et al, 2020b;Zhang et al, 2020a). Finally, the multi-CDK inhibitor dinaciclib blocks the interferon gamma (IFNG)-driven upregulation of PD-L1 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in mouse models of pancreatic adenocarcinomas, ultimately preventing adaptive immune resistance (Huang et al, 2020b).…”