XIAP overexpressing inflammatory breast cancer patients have high infiltration of immunosuppressive subsets and increased TNFR1 signaling targetable with Birinapant.

Autor:	Van Berckelaer C; Multidisciplinary Breast Clinic, Antwerp University Hospital (UZA), Molecular Imaging, Pathology, Radiotherapy, Oncology (MIPRO); Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Duke Consortium for Inflammatory Breast Cancer, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA., Van Laere S; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium., Lee S; Department of Surgery, Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, USA; Duke Consortium for Inflammatory Breast Cancer, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA., Morse MA; Department of Surgery, Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, USA; Duke Consortium for Inflammatory Breast Cancer, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA., Geradts J; Duke Consortium for Inflammatory Breast Cancer, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA; Department of Pathology, Duke University School of Medicine, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA; Department of Pathology, East Carolina University Brody School of Medicine, Greenville, NC, USA., Dirix L; Department of Oncology, GZA Hospitals, University of Antwerp, Antwerpen, Belgium., Kockx M; CellCarta, Antwerp, Belgium., Bertucci F; Predictive Oncology team, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, CNRS, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France., Van Dam P; Multidisciplinary Breast Clinic, Antwerp University Hospital (UZA), Molecular Imaging, Pathology, Radiotherapy, Oncology (MIPRO); Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium. Electronic address: Peter.vandam@uza.be., Devi GR; Department of Surgery, Division of Surgical Sciences, Duke University School of Medicine, Durham, NC, USA; Duke Consortium for Inflammatory Breast Cancer, Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA; Department of Pathology, Duke University School of Medicine, Durham, NC, USA. Electronic address: gayathri.devi@duke.edu.
Jazyk:	angličtina
Zdroj:	Translational oncology [Transl Oncol] 2024 May; Vol. 43, pp. 101907. Date of Electronic Publication: 2024 Feb 27.
DOI:	10.1016/j.tranon.2024.101907
Abstrakt:	Objective: To assess the expression pattern of X-linked inhibitor of apoptosis protein (XIAP), a cellular stress sensor, and delineate the associated changes in the tumor immune microenvironment (TiME) for prognostic value and new therapeutic targets in inflammatory breast cancer (IBC). Methods: Immunohistochemistry was conducted to assess the spatial localization of immune subsets, XIAP, and PDL1 expression in IBC and non-inflammatory breast cancer (nIBC) pretreatment tumors (n = 142). Validation and further exploration were performed by gene expression analysis of patient tumors along with signaling studies in a co-culture model. Results: High XIAP in 37/81 IBC patients correlated significantly with high PD-L1, increased infiltration of FOXP3+ Tregs, CD163+ tumor-associated macrophages (TAMs), low CD8/CD163 ratio in both tumor stroma (TS) and invasive margins (IM), and higher CD8+ T cells and CD79α+ B cells in the IM. Gene set enrichment analysis identified cellular stress response- and inflammation-related genes along with tumor necrosis factor receptor 1 (TNFR1) expression in high-XIAP IBC tumors. Induction of TNFR1 and XIAP was observed when patient-derived SUM149 IBC cells were co-cultured with human macrophage-conditioned media simulating TAMs, further demonstrating that the TNF-α signaling pathway is a likely candidate governing TAM-induced XIAP overexpression in IBC cells. Finally, addition of Birinapant, a pan IAP antagonist, induced cell death in the pro-survival cytokine-enriched conditions. Conclusion: Using immunophenotyping and gene expression analysis in patient biospecimens along with in silico modeling and a preclinical model with a pan-IAP antagonist, this study revealed an interplay between increased TAMs, TNF-α signaling, and XIAP activation during (immune) stress in IBC. These data demonstrate the potential of IAP antagonists as immunomodulators for improving IBC therapeutic regimens. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu