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; Trp53^L/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.

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。