MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models
Journal
International journal of molecular sciences
Journal Volume
22
Journal Issue
17
Date Issued
2021-08-25
Author(s)
Tan, Choon Ping
Reebye, Vikash
Chee, Cheng Ean
Zacharoulis, Dimitris
Habib, Robert
Blakey, David C
Rossi, John J
Habib, Nagy
Sodergren, Mikael H
Abstract
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.
Subjects
CEBPA; PD-1; abscopal; immunotherapy
SDGs
Other Subjects
CCAAT enhancer binding protein; CEBPA protein, mouse; double stranded RNA; animal; Bagg albino mouse; cell culture; colon tumor; drug effect; genetics; immunology; liver cell carcinoma; liver tumor; metabolism; mouse; radiofrequency ablation; tumor associated leukocyte; tumor cell line; tumor microenvironment; Animals; Carcinoma, Hepatocellular; CCAAT-Enhancer-Binding Proteins; Cell Line, Tumor; Cells, Cultured; Colonic Neoplasms; Immune Checkpoint Inhibitors; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Inbred BALB C; Radiofrequency Ablation; RNA, Double-Stranded; Tumor Microenvironment
Type
journal article