Please use this identifier to cite or link to this item:
Title: Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer
Authors: Hashimoto, A
Sarker, D
Reebye, V
Jarvis, S
Sodergren, MH
Kossenkov, A
Sanseviero, E
Raulf, N
Vasara, J
Andrikakou, P
Meyer, T
Huang, KW
Plummer, R
Chee, CE 
Spalding, D
Pai, M
Khan, S
Pinato, DJ
Sharma, R
Basu, B
Palmer, D
Ma, YT
Evans, J
Habib, R
Martirosyan, A
Elasri, N
Reynaud, A
Rossi, JJ
Cobbold, M
Habib, NA
Gabrilovich, DI
Issue Date: 15-Nov-2021
Publisher: American Association for Cancer Research (AACR)
Citation: Hashimoto, A, Sarker, D, Reebye, V, Jarvis, S, Sodergren, MH, Kossenkov, A, Sanseviero, E, Raulf, N, Vasara, J, Andrikakou, P, Meyer, T, Huang, KW, Plummer, R, Chee, CE, Spalding, D, Pai, M, Khan, S, Pinato, DJ, Sharma, R, Basu, B, Palmer, D, Ma, YT, Evans, J, Habib, R, Martirosyan, A, Elasri, N, Reynaud, A, Rossi, JJ, Cobbold, M, Habib, NA, Gabrilovich, DI (2021-11-15). 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) : 5961-5978. ScholarBank@NUS Repository.
Abstract: Purpose: 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. Experimental Design: 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). Results: 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. Conclusions: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPa 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).
Source Title: Clinical Cancer Research
ISSN: 10780432
DOI: 10.1158/1078-0432.CCR-21-0986
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
Upregulation of C:EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.Hashimoto et al.CCR.2021.pdfPublished version1.55 MBAdobe PDF



Google ScholarTM



Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.