Delineating the interplay between oncogenic pathways and immunity in anaplastic Wilms tumors

Xiaoping Su, Xiaofan Lu, Sehrish Khan Bazai, Linda Dainese, Arnauld Verschuur, Benoit Dumont, Roger Mouawad, Li Xu, Wenxuan Cheng, Fangrong Yan, Sabine Irtan, Véronique Lindner, Catherine Paillard, Yves Bouc, Aurore Coulomb () and Gabriel G. Malouf ()
Additional contact information
Xiaoping Su: The University of Texas MD Anderson Cancer Center
Xiaofan Lu: Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Sehrish Khan Bazai: Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA
Linda Dainese: Sorbonne Université
Arnauld Verschuur: Hôpital d’Enfants de La Timone
Benoit Dumont: Centre Léon Bérard, Institut d’Hématologie et d’Oncologie Pédiatrique (IHOPe)
Roger Mouawad: Assistance-Publique Hôpitaux de Paris
Li Xu: China Pharmaceutical University
Wenxuan Cheng: China Pharmaceutical University
Fangrong Yan: China Pharmaceutical University
Sabine Irtan: Sorbonne Université
Véronique Lindner: CHRU Strasbourg
Catherine Paillard: Strasbourg Université
Yves Bouc: Sorbonne Université
Aurore Coulomb: Sorbonne Université
Gabriel G. Malouf: Department of Cancer and Functional Genomics, Institute of Genetics and Molecular and Cellular Biology, CNRS/INSERM/UNISTRA

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Wilms tumors are highly curable in up to 90% of cases with a combination of surgery and radio-chemotherapy, but treatment-resistant types such as diffuse anaplastic Wilms tumors pose significant therapeutic challenges. Our multi-omics profiling unveils a distinct desert-like diffuse anaplastic Wilms tumor subtype marked by immune/stromal cell depletion, TP53 alterations, and cGAS-STING pathway downregulation, accounting for one-third of all diffuse anaplastic cases. This subtype, also characterized by reduced CD8 and CD3 infiltration and active oncogenic pathways involving histone deacetylase and DNA repair, correlates with poor clinical outcomes. These oncogenic pathways are found to be conserved in anaplastic Wilms tumor cell models. We identify histone deacetylase and/or WEE1 inhibitors as potential therapeutic vulnerabilities in these tumors, which might also restore tumor immunogenicity and potentially enhance the effects of immunotherapy. These insights offer a foundation for predicting outcomes and personalizing treatment strategies for aggressive pediatric Wilms tumors, tailored to individual immunological landscapes.

Date: 2023
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DOI: 10.1038/s41467-023-43290-3

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