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

Publication ,  Journal Article
Van Berckelaer, C; Van Laere, S; Lee, S; Morse, MA; Geradts, J; Dirix, L; Kockx, M; Bertucci, F; Van Dam, P; Devi, GR
Published in: Transl Oncol
May 2024

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.

Duke Scholars

Published In

Transl Oncol

DOI

ISSN

1936-5233

Publication Date

May 2024

Volume

43

Start / End Page

101907

Location

United States

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology
 

Citation

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Van Berckelaer, C., Van Laere, S., Lee, S., Morse, M. A., Geradts, J., Dirix, L., … Devi, G. R. (2024). XIAP overexpressing inflammatory breast cancer patients have high infiltration of immunosuppressive subsets and increased TNFR1 signaling targetable with Birinapant. Transl Oncol, 43, 101907. https://doi.org/10.1016/j.tranon.2024.101907
Van Berckelaer, Christophe, Steven Van Laere, Seayoung Lee, Michael A. Morse, Joseph Geradts, Luc Dirix, Mark Kockx, François Bertucci, Peter Van Dam, and Gayathri R. Devi. “XIAP overexpressing inflammatory breast cancer patients have high infiltration of immunosuppressive subsets and increased TNFR1 signaling targetable with Birinapant.Transl Oncol 43 (May 2024): 101907. https://doi.org/10.1016/j.tranon.2024.101907.
Van Berckelaer, Christophe, et al. “XIAP overexpressing inflammatory breast cancer patients have high infiltration of immunosuppressive subsets and increased TNFR1 signaling targetable with Birinapant.Transl Oncol, vol. 43, May 2024, p. 101907. Pubmed, doi:10.1016/j.tranon.2024.101907.
Van Berckelaer C, Van Laere S, Lee S, Morse MA, Geradts J, Dirix L, Kockx M, Bertucci F, Van Dam P, Devi GR. 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.
Journal cover image

Published In

Transl Oncol

DOI

ISSN

1936-5233

Publication Date

May 2024

Volume

43

Start / End Page

101907

Location

United States

Related Subject Headings

  • Oncology & Carcinogenesis
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology