BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras -Mutant Non-Small Cell Lung Cancer

• Published in: Cancer immunology research Vol. 6; no. 10; p. 1234
• Main Authors: Adeegbe, Dennis O, Liu, Shengwu, Hattersley, Maureen M, Bowden, Michaela, Zhou, Chensheng W, Li, Shuai, Vlahos, Raven, Grondine, Michael, Dolgalev, Igor, Ivanova, Elena V, Quinn, Max M, Gao, Peng, Hammerman, Peter S, Bradner, James E, Diehl, J Alan, Rustgi, Anil K, Bass, Adam J, Tsirigos, Aristotelis, Freeman, Gordon J, Chen, Huawei, Wong, Kwok-Kin
• Format: Journal Article
• Language: English
• Published: United States 01.10.2018
• DOI: 10.1158/2326-6066.CIR-18-0077

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 mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of -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 ; (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. .