MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models.
MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models.
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DOI：
10.3390/ijms22179168
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发表时间：
2021-08-25
影响因子：
5.6
通讯作者：
Sodergren MH
中科院分区：
文献类型：
--
作者：
Huang KW;Tan CP;Reebye V;Chee CE;Zacharoulis D;Habib R;Blakey DC;Rossi JJ;Habib N;Sodergren MH
转录因子CEBPA是肝脏稳态、骨髓细胞分化的主要调节因子，并且在几种致癌疾病中下调。MTL-CEBPA是一种小分子激活RNA药物，可上调CEBPA基因表达，用于治疗肝细胞癌（HCC）。我们通过在两个临床前模型中将MTL-CEBPA与抗PD-1检查点抑制剂（CPI）和/或射频消融（RFA）组合来研究MTL-CEBPA是否具有免疫调节作用。首先，用RFA（右侧腹）、抗PD-1或MTL-CEBPA的组合治疗具有两个HCC肿瘤侧腹（BNL）的小鼠。在RFA+抗PD 1 +MTL-CEBPA治疗组中，左侧腹侧肿瘤的减少最明显，7/8只动物有反应。这是唯一一个CD 8+和CD 49 b +/CD 45+肿瘤浸润淋巴细胞（TIL）显著增加的组。第二，在CT 26结肠癌模型中测试了抗PD-1+MTL-CEBPA的组合，该治疗显著减小了肿瘤大小，调节了肿瘤免疫微环境并增加了TIL。这些数据表明，CPI、RFA和MTL-CEBPA联合治疗的临床作用是通过协同引发免疫肿瘤反应，使RFA和CPI具有显著的抗肿瘤作用，包括RFA在未治疗肿瘤中的活性。
The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models. First, mice with two flanks of HCC tumors (BNL) were treated with combinations of RFA (right flank), anti-PD-1 or MTL-CEBPA. The reduction of the left flank tumors was most pronounced in the group treated with RFA+anti-PD1+MTL-CEBPA and 7/8 animals responded. This was the only group with a significant increase in CD8+ and CD49b+/CD45+ tumor infiltrating lymphocytes (TIL). Second, a combination of anti-PD-1+MTL-CEBPA was tested in a CT26 colon cancer model and this treatment significantly reduced tumor size, modulated the tumor immune microenvironment and increased TILs. These data suggest a clinical role for combination treatment with CPIs, RFA and MTL-CEBPA through synergistic priming of the immune tumor response, enabling RFA and CPIs to have a pronounced anti-tumor effect including activity in non-treated tumors in the case of RFA.
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影响因子：
2.8
作者：
Setten RL;Lightfoot HL;Habib NA;Rossi JJ
通讯作者：
Rossi JJ
DOI：
10.1002/hep.26669
发表时间：
2014-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Reebye V;Sætrom P;Mintz PJ;Huang KW;Swiderski P;Peng L;Liu C;Liu X;Lindkaer-Jensen S;Zacharoulis D;Kostomitsopoulos N;Kasahara N;Nicholls JP;Jiao LR;Pai M;Spalding DR;Mizandari M;Chikovani T;Emara MM;Haoudi A;Tomalia DA;Rossi JJ;Habib NA
通讯作者：
Habib NA
影响因子：
--
作者：
Qi X;Zhao Y;Li H;Guo X;Han G
通讯作者：
Han G
影响因子：
4.6
作者：
Mackert JR;Qu P;Min Y;Johnson PF;Yang L;Lin PC
通讯作者：
Lin PC
影响因子：
--
作者：
Evrard, Serge;Menetrier-Crux, Christine;Rosenbaum, Jean
通讯作者：
Rosenbaum, Jean