{"doi":"10.1016/j.tranon.2024.101907","title":"XIAP overexpressing inflammatory breast cancer patients have high infiltration of immunosuppressive subsets and increased TNFR1 signaling targetable with Birinapant","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.","journal":"Translational Oncology","year":2024,"id":439818,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.953,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":935690,"name":"Steven Van Laere","orcid":"0000-0002-2640-0040","position":1,"is_corresponding":false},{"id":1251517,"name":"Seayoung Lee","orcid":null,"position":2,"is_corresponding":false},{"id":905121,"name":"Michael A. Morse","orcid":"0000-0002-5725-4533","position":3,"is_corresponding":false},{"id":256298,"name":"Joseph Geradts","orcid":"0009-0002-3817-8499","position":4,"is_corresponding":false},{"id":13410,"name":"Luc Dirix","orcid":null,"position":5,"is_corresponding":false},{"id":1251103,"name":"Mark Kockx","orcid":"0000-0001-9147-2975","position":6,"is_corresponding":false},{"id":582576,"name":"François Bertucci","orcid":"0000-0002-0157-0959","position":7,"is_corresponding":false},{"id":868756,"name":"Peter A. van Dam","orcid":"0000-0002-9184-7703","position":8,"is_corresponding":false},{"id":88913,"name":"Gayathri R. Devi","orcid":"0000-0001-9158-7289","position":9,"is_corresponding":false},{"id":1251102,"name":"Christophe Van Berckelaer","orcid":"0000-0003-4082-9799","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:00:52.633010Z","pmid":"38412664","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}