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BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras-Mutant Non–Small Cell Lung Cancer
Cancer Immunology Research ( IF 8.1 ) Pub Date : 2018-10-01 , DOI: 10.1158/2326-6066.cir-18-0077
Dennis O. Adeegbe 1 , Shengwu Liu 2, 3 , Maureen M. Hattersley 4 , Michaela Bowden 2 , Chensheng W. Zhou 2 , Shuai Li 2, 5 , Raven Vlahos 2 , Michael Grondine 4 , Igor Dolgalev 6 , Elena V. Ivanova 2, 7 , Max M. Quinn 2 , Peng Gao 2 , Peter S. Hammerman 8 , James E. Bradner 8 , J. Alan Diehl 9 , Anil K. Rustgi 10 , Adam J. Bass 2 , Aristotelis Tsirigos 6 , Gordon J. Freeman 2 , Huawei Chen 4 , Kwok-Kin Wong 1
Affiliation  

KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances in targeted therapy have shown great promise, effective targeting of KRAS remains elusive, and concurrent alterations in tumor suppressors render KRAS-mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS-mutant tumors are immunosuppressive mechanisms, such as increased presence of suppressive regulatory T cells (Treg) in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells. Treatment with BET bromodomain inhibitors is beneficial for hematologic malignancies, and they have Treg-disruptive effects in a non–small cell lung cancer (NSCLC) model. Targeting PD-1–inhibitory signals through PD-1 antibody blockade also has substantial therapeutic impact in lung cancer, although these outcomes are limited to a minority of patients. We hypothesized that the BET bromodomain inhibitor JQ1 would synergize with PD-1 blockade to promote a robust antitumor response in lung cancer. In the present study, using Kras+/LSL-G12D; Trp53L/L (KP) mouse models of NSCLC, we identified cooperative effects between JQ1 and PD-1 antibody. The numbers of tumor-infiltrating Tregs were reduced and activation of tumor-infiltrating T cells, which had a T-helper type 1 (Th1) cytokine profile, was enhanced, underlying their improved effector function. Furthermore, lung tumor–bearing mice treated with this combination showed robust and long-lasting antitumor responses compared with either agent alone, culminating in substantial improvement in the overall survival of treated mice. Thus, combining BET bromodomain inhibition with immune checkpoint blockade offers a promising therapeutic approach for solid malignancies such as lung adenocarcinoma. Cancer Immunol Res; 6(10); 1234–45. ©2018 AACR.



中文翻译:

BET溴结构域抑制作用与PD-1阻断作用共同促进Kras突变型非小细胞肺癌的抗肿瘤反应

KRAS突变存在于约30%的人肺腺癌中。尽管靶向治疗的最新进展显示出了广阔的前景,但有效靶向KRAS仍然遥遥无期,并且肿瘤抑制因子的同时改变使得KRAS突变型肿瘤对现有疗法的耐药性更高。促进KRAS的耐火度突变型肿瘤是免疫抑制机制,例如肿瘤中抑制性调节性T细胞(Treg)的存在增加以及肿瘤浸润性T细胞上抑制性受体PD-1的表达升高。BET溴结构域抑制剂治疗对血液系统恶性肿瘤有益,并且在非小细胞肺癌(NSCLC)模型中具有Treg破坏作用。通过PD-1抗体阻断靶向PD-1抑制信号在肺癌中也具有重要的治疗作用,尽管这些结果仅限于少数患者。我们假设BET溴结构域抑制剂JQ1将与PD-1阻滞剂协同作用,从而促进肺癌中强大的抗肿瘤反应。在本研究中,使用Kras + / LSL-G12D ; 色氨酸53 L / L(KP)小鼠模型的非小细胞肺癌,我们确定了JQ1和PD-1抗体之间的协同作用。减少了肿瘤浸润性Treg的数量,并增强了具有T型辅助1型(Th1)细胞因子特征的肿瘤浸润性T细胞的激活,这是其改善的效应子功能的基础。此外,与单独使用任何一种药物相比,用这种组合治疗的荷瘤小鼠均显示出强大而持久的抗肿瘤反应,最终使所治疗小鼠的整体存活率显着提高。因此,将BET溴结构域抑制作用与免疫检查点封锁相结合,为诸如肺腺癌等实体恶性肿瘤提供了一种有前途的治疗方法。癌症免疫研究;6(10); 1234–45。©2018 AACR

更新日期:2018-10-02
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