Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer
Hashimoto, A Sarker, D Reebye, V Jarvis, S Sodergren, MH Kossenkov, A Sanseviero, E Raulf, N Vasara, J Andrikakou, P
Hashimoto, A
Sarker, D
Reebye, V
Jarvis, S
Sodergren, MH
Kossenkov, A
Sanseviero, E
Raulf, N
Vasara, J
Andrikakou, P
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Alternative Title
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).
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Source Title
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
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Date
2021-11-15
DOI
10.1158/1078-0432.CCR-21-0986
Type
Article