Hashimoto, Ayumi, Sarker, Debashis, Reebye, Vikash, Jarvis, Sheba, Sodergren, Mikael H, Kossenkov, Andrew, Sanseviero, Emilio, Raulf, Nina, Vasara, Jenni, Andrikakou, Pinelopi et al (show 21 more authors)
(2021)
Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.
CLINICAL CANCER RESEARCH, 27 (21).
pp. 5961-5978.
Abstract
<h4>Purpose</h4>To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models.<h4>Experimental design</h4>We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38).<h4>Results</h4>MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy.<h4>Conclusions</h4>This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Tumor Cells, Cultured, Myeloid Cells, Animals, Humans, Mice, Carcinoma, Hepatocellular, Liver Neoplasms, CCAAT-Enhancer-Binding Protein-alpha, Antineoplastic Agents, Treatment Outcome, Up-Regulation, Sorafenib |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 21 Jan 2022 10:23 |
| Last Modified: | 19 Oct 2023 09:05 |
| DOI: | 10.1158/1078-0432.CCR-21-0986 |
| Open Access URL: | https://clincancerres.aacrjournals.org/content/27/... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3147326 |
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