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

Cancer Immunol Res
Authors
Keywords
Abstract

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. .

Year of Publication
2018
Journal
Cancer Immunol Res
Volume
6
Issue
10
Pages
1234-1245
Date Published
2018 10
ISSN
2326-6074
DOI
10.1158/2326-6066.CIR-18-0077
PubMed ID
30087114
PubMed Central ID
PMC6170698
Links
Grant list
R01 CA216188 / CA / NCI NIH HHS / United States
R01 CA219670 / CA / NCI NIH HHS / United States
P01 CA154303 / CA / NCI NIH HHS / United States
R01 CA166480 / CA / NCI NIH HHS / United States
P01 CA098101 / CA / NCI NIH HHS / United States
R01 CA140594 / CA / NCI NIH HHS / United States
U01 CA213333 / CA / NCI NIH HHS / United States
R01 CA205150 / CA / NCI NIH HHS / United States