Data from Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer

• DOI: 10.1158/1078-0432.c.7531354
• Publication Date: 2024-11-08T16:40:17Z
• Authors: 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 Basu; Daniel Palmer; Yuk-Ting Ma; Jeff Evans; Robert Habib; Anna Martirosyan; Naouel Elasri; Adeline Reynaud; John J. Rossi; Mark Cobbold; Nagy A. Habib; Dmitry I. Gabrilo...

<div>AbstractPurpose:<p>To evaluate the mechanisms of how therapeutic upregulation transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and different mouse models.</p>Experimental Design:<p>We conducted a phase I trial 36 HCC (NCT02716012) who received sorafenib as part their standard care, were given C/EBPα small activating RNA (saRNA; MTL-CEBPA) either neoadjuvant or adjuvant treatment. In preclinical setting, effects MTL-CEBPA assessed several models, including BNL-1ME liver cancer, Lewis lung (LLC), colon adenocarcinoma (MC38).</p>Results:<p>MTL-CEBPA treatment caused radiologic regression tumors 26.7% an underlying viral etiology 3 complete responders. those marked decrease peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers overall reduction protumoral M2 tumor-associated macrophages (TAM). Gene analysis patient leukocytes following showed CEBPA activation affected regulation factors involved immune-suppressive activity. To corroborate this observation, all models led to reversal suppressive activity M-MDSCs TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor these dependency on T cells. This was accentuated when combined checkpoint inhibitors PMN-MDSC–targeted immunotherapy.</p>Conclusions:<p>This report demonstrates that factor causes inactivation myeloid cells potent responses across cancer patients. is currently being investigated combination pembrolizumab I/Ib multicenter clinical study (NCT04105335).</p></div>