In a genetically engineered mouse model of KRAS-mutant non-small cell lung cancer with p53 deficiency, Adeegbe et al. utilized the BET bromodomain inhibitor JQI (a drug that has been shown to disrupt Tregs) in combination with anti-PD-1. The combination reduced Tregs (including KLRG1-expressing Tregs), reduced PD-1 expression by TILs, increased the activation and effector activity of TILs, increased MHC-I expression on TAMs, promoted a Th1 cytokine signature in the tumor, decreased expression of growth and survival genes by tumor cells, and led to robust and durable antitumor responses and improved overall survival.

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 (Tregs) 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 to 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.

Author Info: (1) New York University. (2) Department of Medical Oncology, Dana-Farber Cancer Institute. (3) IMED Oncology, AstraZeneca (United States). (4) Center for Molecular Oncologic Pathology, Dana-Farber

Author Info: (1) New York University. (2) Department of Medical Oncology, Dana-Farber Cancer Institute. (3) IMED Oncology, AstraZeneca (United States). (4) Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute. (5) Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute. (6) Dana-Farber Cancer Institute. (7) Department of Medical Oncology, Dana-Farber Cancer Institute. (8) Oncology, AstraZeneca (United States). (9) Applied Bioinformatics Laboratories, NYU School of Medicine. (10) Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute. (11) Department of Medical Oncology, Dana-Farber Cancer Institute. (12) Department of Medical Oncology, Dana-Farber Cancer Institute. (13) Novartis Institutes of Biomedical Research. (14) Department of Medical Oncology, Dana-Farber Cancer Institute. (15) Department of Biochemistry and Molecular Biology, Medical University of South Carolina. (16) Division of Gastroenterology, Departments of Medicine and Genetics, Pancreatic Cancer Translational Center of Excellence, Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine. (17) Department of Medical Oncology, Dana-Farber Cancer Institute. (18) Pathology, NYU Langone Medical Center. (19) Department of Medical Oncology, Dana-Farber Cancer Institute. (20) Oncology, IMED Biotech Unit, AstraZeneca R&D Boston. (21) Perlmutter Cancer Center, New York University Langone Medical Center kwok-kin.wong@nyumc.org.

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