期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 17, 页码 -出版社
MDPI
DOI: 10.3390/ijms22179168
关键词
CEBPA; abscopal; immunotherapy; PD-1
资金
- Ministry of Science and Technology, Taiwan [105-2314-B-002-059-MY3]
Combination treatment with MTL-CEBPA, anti-PD-1 checkpoint inhibitors, and radiofrequency ablation showed promising results in preclinical models by reducing tumor size, modulating the tumor immune microenvironment, and increasing tumor infiltrating lymphocytes, suggesting a potential clinical application in enhancing anti-tumor immunity.
The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models. First, mice with two flanks of HCC tumors (BNL) were treated with combinations of RFA (right flank), anti-PD-1 or MTL-CEBPA. The reduction of the left flank tumors was most pronounced in the group treated with RFA+anti-PD1+MTL-CEBPA and 7/8 animals responded. This was the only group with a significant increase in CD8+ and CD49b+/CD45+ tumor infiltrating lymphocytes (TIL). Second, a combination of anti-PD-1+MTL-CEBPA was tested in a CT26 colon cancer model and this treatment significantly reduced tumor size, modulated the tumor immune microenvironment and increased TILs. These data suggest a clinical role for combination treatment with CPIs, RFA and MTL-CEBPA through synergistic priming of the immune tumor response, enabling RFA and CPIs to have a pronounced anti-tumor effect including activity in non-treated tumors in the case of RFA.
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