Please use this identifier to cite or link to this item: https://doi.org/10.1158/1078-0432.CCR-21-0986
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. https://doi.org/10.1158/1078-0432.CCR-21-0986
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
URI: https://scholarbank.nus.edu.sg/handle/10635/208516
ISSN: 10780432
15573265
DOI: 10.1158/1078-0432.CCR-21-0986
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