Upregulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and patients with cancer

Ayumi Hashimoto, Debashis Sarker, Vikash Reebye*, Sheba Jarvis, Mikael H. Sodergren, Andrew Kossenkov, Emilio Sanseviero, Nina Raulf, Jenni Vasara, Pinelopi Andrikakou, Tim Meyer, Kai Wen Huang, Ruth Plummer, Cheng E. Chee, Duncan Spalding, Madhava Pai, Shahid Khan, David J. Pinato, Rohini Sharma, Bristi BasuDaniel Palmer, Yuk Ting Ma, Jeff Evans, Robert Habib, Anna Martirosyan, Naouel Elasri, Adeline Reynaud, John J. Rossi, Mark Cobbold, Nagy A. Habib, Dmitry I. Gabrilovich

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)5961-5978
Number of pages18
JournalClinical Cancer Research
Volume27
Issue number21
DOIs
Publication statusPublished - 15 Nov 2021

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