Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.

Autor:	Hermida-Prado F; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; University of Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), IUOPA, Oviedo, Spain.; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain., Xie Y; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Sherman S; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Nagy Z; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Russo D; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Akhshi T; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Chu Z; Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah., Feit A; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Campisi M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Chen M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Immunology, Harvard Medical School, Boston, Massachusetts., Nardone A; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Guarducci C; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Lim K; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Font-Tello A; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Lee I; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., García-Pedrero J; University of Oviedo, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), IUOPA, Oviedo, Spain.; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain., Cañadas I; Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Agudo J; Harvard Medical School, Boston, Massachusetts.; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts., Huang Y; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts., Sella T; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts., Jin Q; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Tayob N; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Mittendorf EA; Harvard Medical School, Boston, Massachusetts.; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.; Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts., Tolaney SM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts., Qiu X; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Long H; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts., Symmans WF; Department of Pathology, MD Anderson Cancer Center, Houston, Texas., Lin JR; Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts.; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts., Santagata S; Ludwig Center at Harvard and Laboratory of Systems Pharmacology, Harvard Medical School, Boston, Massachusetts.; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Bedrosian I; Department of Breast Surgical Oncology, Division of Surgery, MD Anderson Cancer Center, Houston, Texas., Yardley DA; Department of Medical Oncology, Sarah Cannon Cancer Center, Nashville, Tennessee.; Tennessee Oncology, Nashville, Tennessee., Mayer IA; Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee., Richardson ET; Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Oliveira G; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Wu CJ; Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Schuster EF; The BC Now Toby Robins Research Centre at the Institute of Cancer Research, London, United Kingdom.; Ralph Lauren Centre for BC Research, Royal Marsden Hospital, London, United Kingdom.; The Royal Marsden Hospital, London, United Kingdom., Dowsett M; The BC Now Toby Robins Research Centre at the Institute of Cancer Research, London, United Kingdom.; Ralph Lauren Centre for BC Research, Royal Marsden Hospital, London, United Kingdom.; The Royal Marsden Hospital, London, United Kingdom., Welm AL; Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah., Barbie D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Metzger O; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts., Jeselsohn R; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2023 Oct 02; Vol. 83 (19), pp. 3284-3304.
DOI:	10.1158/0008-5472.CAN-23-1711
Abstrakt:	Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of β2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I-specific T-cell-mediated cytotoxicity. Remarkably, the combination of ET and SMAC mimetics, which also blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. Significance: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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