Tumor microenvironment mimicking 3D models unveil the multifaceted effects of SMAC mimetics

Small molecule IAP antagonists - SMAC mimetics (SM) - are being developed as an anticancer therapy. SM therapy was demonstrated not only to sensitize tumor cells to TNFα-mediated cell death but also to exert immunostimulatory properties. Their good safety and tolerability profile, plus promising pre...

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Published iniScience Vol. 26; no. 4; p. 106381
Main Authors Pinto, Catarina, Slavic-Obradovic, Ksenija, Fürweger, Daniela, Thaler, Barbara, Souabni, Abdallah, Carotta, Sebastian, Aichinger, Martin, Reiser, Ulrich, Impagnatiello, Maria Antonietta, Tirapu, Iñigo
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 21.04.2023
Elsevier
Subjects
Biological sciences
Cancer
Cancer systems biology
Systems biology
Cancer systems biology
Biological sciences
Systems biology
Cancer
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Summary:Small molecule IAP antagonists - SMAC mimetics (SM) - are being developed as an anticancer therapy. SM therapy was demonstrated not only to sensitize tumor cells to TNFα-mediated cell death but also to exert immunostimulatory properties. Their good safety and tolerability profile, plus promising preclinical data, warrants further investigation into their various effects within the tumor microenvironment. Using in vitro models of human tumor cells and fibroblast spheroids co-cultured with primary immune cells, we investigated the effects of SM on immune cell activation. SM treatment induces the maturation of human PBMC- and patient-derived dendritic cells (DC), and modulates cancer-associated fibroblasts towards an immune interacting phenotype. Finally, SM-induced tumor necroptosis further enhances DC activation, leading also to higher T-cell activation and infiltration into the tumor site. These results highlight the relevance of using heterotypic in vitro models to investigate the effects of targeted therapies on different components of the tumor microenvironment. [Display omitted] •Heterotypic 3D models enable the analysis of targeted therapy effects on the TME•SMAC mimetics (SM) activate PBMC and patient dendritic cells, T cells, and NK cells•SM modulate cancer-associated fibroblasts into an inflammatory status•SM-induced necroptosis enhances DC activation, increasing T cell infiltration Biological sciences; Systems biology; Cancer systems biology; Cancer
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ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.106381