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

• Published in: Translational oncology Vol. 43; p. 101907
• Main Authors: Van Berckelaer, Christophe, Van Laere, Steven, Lee, Seayoung, Morse, Michael A, Geradts, Joseph, Dirix, Luc, Kockx, Mark, Bertucci, François, Van Dam, Peter, Devi, Gayathri R
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2024; Elsevier
• Subjects: Birinapant, IAP-antagonist; Inflammatory breast cancer (IBC); PD-L1; Tumor immune-microenvironment (TiME); Tumor necrosis factor - alpha (TNF-α); Tumor-associated macrophages (TAM); XIAP; Tumor-associated macrophages (TAM); Birinapant, IAP-antagonist; PD-L1; XIAP; Tumor necrosis factor - alpha (TNF-α); Tumor immune-microenvironment (TiME); Inflammatory breast cancer (IBC)
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2024.101907

•Inflammatory Breast Cancer is a rare but highly aggressive variant responsible for 10 % of breast cancer-related mortality.•XIAP is involved in the regulation of programmed cell death.•In IBC, XIAP is associated with more tumor associated macrophages and an immunosuppressive tumor microenvironment.•The TNF-a signaling pathway is a likely candidate governing macrophage-induced XIAP overexpression in IBC.•Birinapant, a pan IAP antagonist, induced apoptotic signals by decreasing XIAP and has potential as therapy to overcome an immunosuppressive tumor microenvironment. 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). 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. 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. 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.