B7-H1 Antigen; Immune Checkpoint Inhibitors; Nuclear Proteins; Transcription Factors; Paclitaxel; Humans; Animals; Mice; B7-H1 Antigen/metabolism; Immune Checkpoint Inhibitors/therapeutic use; Paclitaxel/pharmacology; Paclitaxel/therapeutic use; Immunotherapy/methods; Triple Negative Breast Neoplasms/pathology; Immunotherapy; Triple Negative Breast Neoplasms; Oncology; Cancer Research
Abstract :
[en] Immune checkpoint inhibition combined with chemotherapy is currently approved as first-line treatment for patients with advanced PD-L1-positive triple-negative breast cancer (TNBC). However, a significant proportion of metastatic TNBC is PD-L1-negative and, in this population, chemotherapy alone largely remains the standard-of-care and novel therapeutic strategies are needed to improve clinical outcomes. Here, we describe a triple combination of anti-PD-L1 immune checkpoint blockade, epigenetic modulation thorough bromodomain and extra-terminal (BET) bromodomain inhibition (BBDI), and chemotherapy with paclitaxel that effectively inhibits both primary and metastatic tumor growth in two different syngeneic murine models of TNBC. Detailed cellular and molecular profiling of tumors from single and combination treatment arms revealed increased T- and B-cell infiltration and macrophage reprogramming from MHCIIlow to a MHCIIhigh phenotype in mice treated with triple combination. Triple combination also had a major impact on gene expression and chromatin profiles shifting cells to a more immunogenic and senescent state. Our results provide strong preclinical evidence to justify clinical testing of BBDI, paclitaxel, and immune checkpoint blockade combination.
Disciplines :
Oncology
Author, co-author :
Alečković, Maša ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts ; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Li, Zheqi ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts ; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Zhou, Ningxuan ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Harvard University, Cambridge, Massachusetts
Qiu, Xintao ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Harvard University, Cambridge, Massachusetts
Lulseged, Bethlehem ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts
Foidart, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts ; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Huang, Xiao-Yun ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Garza, Kodie ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Shu, Shaokun ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts ; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Kesten, Nikolas ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Harvard University, Cambridge, Massachusetts
Li, Rong ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Harvard University, Cambridge, Massachusetts
Lim, Klothilda ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Harvard University, Cambridge, Massachusetts
Garrido-Castro, Ana C ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts ; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Guerriero, Jennifer L ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Department of Surgery, Division of Breast Surgery, Brigham and Women's Hospital, Boston, Massachusetts
Qi, Jun ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts ; Department of Medicine, Harvard Medical School, Boston, Massachusetts
Long, Henry W ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Harvard University, Cambridge, Massachusetts
Polyak, Kornelia ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts ; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts ; Department of Medicine, Harvard Medical School, Boston, Massachusetts
NCI - National Cancer Institute Susan G. Komen Breast Cancer Foundation
Funding text :
We thank members of the Polyak laboratory for their critical reading of the article and useful advice. Financial support: Funded by the NCI R35 CA197623 (K. Polyak), P50 CA168504 (J.L. Guerriero, K. Polyak), P01CA250959 (K. Polyak, H.W. Long), the Ludwig Center at Harvard (K. Polyak), and the Susan G. Komen Foundation PDF14302777 (S. Shu).
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