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

被引：63

作者：

Hashimoto, Ayumi ^{[1
,2
]}

Sarker, Debashis ^{[3
]}

Reebye, Vikash ^{[4
,5
]}

Jarvis, Sheba ^{[4
]}

Sodergren, Mikael H. ^{[4
]}

Kossenkov, Andrew ^{[1
]}

Sanseviero, Emilio ^{[1
]}

Raulf, Nina ^{[5
]}

Vasara, Jenni ^{[5
]}

Andrikakou, Pinelopi ^{[4
]}

Meyer, Tim ^{[6
]}

Huang, Kai-Wen ^{[7
]}

Plummer, Ruth ^{[8
,9
]}

Chee, Cheng E. ^{[10
]}

Spalding, Duncan ^{[4
]}

Pai, Madhava ^{[4
]}

Khan, Shahid ^{[4
]}

Pinato, David J. ^{[4
]}

Sharma, Rohini ^{[4
]}

Basu, Bristi ^{[11
]}

Palmer, Daniel ^{[12
,13
]}

Ma, Yuk-Ting ^{[14
,15
]}

Evans, Jeff ^{[16
]}

Habib, Robert ^{[5
]}

Martirosyan, Anna ^{[17
]}

Elasri, Naouel ^{[17
]}

Reynaud, Adeline ^{[17
]}

Rossi, John J. ^{[18
]}

Cobbold, Mark ^{[2
]}

Habib, Nagy A. ^{[4
]}

Gabrilovich, Dmitry I. ^{[2
,5
]}

机构：

[1] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA

[2] AstraZeneca, One Medimmune Way, Gaithersburg, MD 20878 USA

[3] Kings Coll London, London, England

[4] Imperial Coll London, London, England

[5] MiNA Therapeut Ltd, London, England

[6] UCL, Inst Canc, London, England

[7] Natl Taiwan Univ, Taipei, Taiwan

[8] Northern Ctr Canc Care, Newcastle Upon Tyne, Tyne & Wear, England

[9] Newcastle Univ, Newcastle Upon Tyne, Tyne & Wear, England

[10] Natl Univ Canc Inst Singapore, Singapore, Singapore

[11] Univ Cambridge, Cambridge, England

[12] Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England

[13] Clatterbridge Canc Ctr, Liverpool, Merseyside, England

[14] Univ Birmingham, Birmingham, W Midlands, England

[15] Univ Hosp Birmingham NHS Trust, Birmingham, W Midlands, England

[16] Univ Glasgow, Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland

[17] HalioDx, Marseille, France

[18] Beckman Res Inst City Hope, Dept Mol & Cellular Biol, Duarte, CA USA

来源：

CLINICAL CANCER RESEARCH | 2021年 / 27卷 / 21期

关键词：

BINDING PROTEIN ALPHA; HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION; SORAFENIB; IDENTIFICATION; MACROPHAGES; NEUTROPHILS; CEBPA;

D O I：

10.1158/1078-0432.CCR-21-0986

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBP alpha), 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/EBP alpha 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/EBP alpha 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).

引用

页码：5961 / 5978

页数：18

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