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

Christophe Van Berckelaer; Steven Van Laere; Seayoung Lee; Michael A Morse; Joseph Geradts; Luc Dirix; Mark Kockx; François Bertucci; Peter Van Dam; Gayathri R Devi

doi:10.1016/j.tranon.2024.101907

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

Transl Oncol. 2024 May:43:101907. doi: 10.1016/j.tranon.2024.101907. Epub 2024 Feb 27.

Authors

Affiliations

¹ 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.
² Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
³ 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.
⁴ 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.
⁵ 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.
⁶ Department of Oncology, GZA Hospitals, University of Antwerp, Antwerpen, Belgium.
⁷ CellCarta, Antwerp, Belgium.
⁸ Predictive Oncology team, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, CNRS, Aix-Marseille Université, Institut Paoli-Calmettes, Marseille, France.
⁹ 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.
¹⁰ 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.

Abstract

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.

Keywords: Birinapant, IAP-antagonist; Inflammatory breast cancer (IBC); PD-L1; Tumor immune-microenvironment (TiME); Tumor necrosis factor - alpha (TNF-α); Tumor-associated macrophages (TAM); XIAP.