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Inhibition of DCLK1 with DCLK1-IN-1 Suppresses Renal Cell Carcinoma Invasion and Stemness and Promotes Cytotoxic T-Cell-Mediated Anti-Tumor Immunity
| Content Provider | MDPI |
|---|---|
| Author | Ding, Ling Yang, Yuning Ge, Yang Lu, Qin Yan, Zixing Chen, Xuzheng Du, Jian Hafizi, Sassan Xu, Xiaohui Yao, Jiannan Liu, Jian Cao, Zhiyun Weygant, Nathaniel |
| Copyright Year | 2021 |
| Description | The approval of immune checkpoint inhibitors has expanded treatment options for renal cell carcinoma (RCC), but new therapies that target RCC stemness and promote anti-tumor immunity are needed. Previous findings demonstrate that doublecortin-like kinase 1 (DCLK1) regulates stemness and is associated with RCC disease progression. Herein, we demonstrate that small-molecule kinase inhibitor DCLK1-IN-1 strongly inhibits DCLK1 phosphorylation and downregulates pluripotency factors and cancer stem cell (CSC) or epithelial-mesenchymal transition (EMT)-associated markers including c-MET, c-MYC, and N-Cadherin in RCC cell lines. Functionally, DCLK1-IN-1 treatment resulted in significantly reduced colony formation, migration, and invasion. Additionally, assays using floating or Matrigel spheroid protocols demonstrated potent inhibition of stemness. An analysis of clinical populations showed that DCLK1 predicts RCC survival and that its expression is correlated with reduced CD8+ cytotoxic T-cell infiltration and increases in M2 immunosuppressive macrophage populations. The treatment of RCC cells with DCLK1-IN-1 significantly reduced the expression of immune checkpoint ligand PD-L1, and co-culture assays using peripheral blood monocytes (PBMCs) or T-cell expanded PBMCs demonstrated a significant increase in immune-mediated cytotoxicity alone or in combination with anti-PD1 therapy. Together, these findings demonstrate broad susceptibility to DCLK1 kinase inhibition in RCC using DCLK1-IN-1 and provide the first direct evidence for DCLK1-IN-1 as an immuno-oncology agent. |
| Starting Page | 5729 |
| e-ISSN | 20726694 |
| DOI | 10.3390/cancers13225729 |
| Journal | Cancers |
| Issue Number | 22 |
| Volume Number | 13 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2021-11-16 |
| Access Restriction | Open |
| Subject Keyword | Cancers Oncology Urology and Nephrology Dclk1 Pd-l1 Dclk1-in-1 Renal Cell Carcinoma Csc Immune Checkpoint Inhibitor Ici Immunotherapy Kinase Inhibitor Combination Therapy |
| Content Type | Text |
| Resource Type | Article |
