Up-regulation of C/EBPα inhibits suppressive activity of myeloid cells and potentiates antitumor response in mice and cancer patients
2021
Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, 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, who received Sorafenib as part of their standard care, and were given therapeutic C/EBPα saRNA (MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the pre-clinical setting the effects of MTL-CEBPA were assessed in several mouse models. Results: MTL-CEBPA treatment caused radiological tumor regression in 26.7% of HCC patients with an underlying viral etiology with three 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 pro-tumoral 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 MDSC (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 immuno-therapy. Conclusions: We show that therapeutic up-regulation of 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 1/1b multi-center clinical study.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
39
References
2
Citations
NaN
KQI