Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 11 2021
01 11 2021
Historique:
received:
17
03
2021
revised:
21
06
2021
accepted:
16
08
2021
pubmed:
20
8
2021
medline:
1
4
2022
entrez:
19
8
2021
Statut:
ppublish
Résumé
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. 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). 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. This report demonstrates that therapeutic upregulation of the transcription factor 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 I/Ib multicenter clinical study (NCT04105335).
Identifiants
pubmed: 34407972
pii: 1078-0432.CCR-21-0986
doi: 10.1158/1078-0432.CCR-21-0986
pmc: PMC8756351
mid: NIHMS1765432
doi:
Substances chimiques
Antineoplastic Agents
0
CCAAT-Enhancer-Binding Protein-alpha
0
Sorafenib
9ZOQ3TZI87
Banques de données
ClinicalTrials.gov
['NCT04105335']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5961-5978Subventions
Organisme : Cancer Research UK
ID : 26813
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA211199
Pays : United States
Organisme : Cancer Research UK
ID : 11650
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P50 CA168536
Pays : United States
Informations de copyright
©2021 The Authors; Published by the American Association for Cancer Research.
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