PT  - JOURNAL ARTICLE
AU  - Adeegbe, Dennis O.
AU  - Liu, Shengwu
AU  - Hattersley, Maureen M.
AU  - Bowden, Michaela
AU  - Zhou, Chensheng W.
AU  - Li, Shuai
AU  - Vlahos, Raven
AU  - Grondine, Michael
AU  - Dolgalev, Igor
AU  - Ivanova, Elena V.
AU  - Quinn, Max M.
AU  - Gao, Peng
AU  - Hammerman, Peter S.
AU  - Bradner, James E.
AU  - Diehl, J. Alan
AU  - Rustgi, Anil K.
AU  - Bass, Adam J.
AU  - Tsirigos, Aristotelis
AU  - Freeman, Gordon J.
AU  - Chen, Huawei
AU  - Wong, Kwok-Kin
TI  - BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in <em>Kras</em>-Mutant Non–Small Cell Lung Cancer
AID  - 10.1158/2326-6066.CIR-18-0077
DP  - 2018 Oct 01
TA  - Cancer Immunology Research
PG  - 1234--1245
VI  - 6
IP  - 10
4099  - http://cancerimmunolres.aacrjournals.org/content/6/10/1234.short
4100  - http://cancerimmunolres.aacrjournals.org/content/6/10/1234.full
SO  - Cancer Immunol Res2018 Oct 01; 6
AB  - 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.