Combination Therapies to Improve the Efficacy of Immunotherapy in Triple-negative Breast Cancer.

Autor:	Alečković M; 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 Z; 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 N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard University, Cambridge, Massachusetts., Qiu X; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard University, Cambridge, Massachusetts., Lulseged B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Foidart P; 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 XY; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Garza K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Shu S; 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 N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard University, Cambridge, Massachusetts., Li R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard University, Cambridge, Massachusetts., Lim K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard University, Cambridge, Massachusetts., Garrido-Castro AC; 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 JL; 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 J; 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 HW; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard University, Cambridge, Massachusetts., Polyak K; 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.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2023 Nov 01; Vol. 22 (11), pp. 1304-1318.
DOI:	10.1158/1535-7163.MCT-23-0303
Abstrakt:	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. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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