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Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma

Author

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  • Dimitra Kerdidani

    (Biomedical Sciences Research Center Alexander Fleming
    National and Kapodistrian University of Athens)

  • Panagiotis Chouvardas

    (Biomedical Sciences Research Center Alexander Fleming
    University of Bern
    University of Bern)

  • Ares Rocanin Arjo

    (Integrative Biology of Human Dendritic Cells and T Cells, Institute Curie)

  • Ioanna Giopanou

    (University of Patras, Rio)

  • Giannoula Ntaliarda

    (University of Patras, Rio)

  • Yu Amanda Guo

    (Genome Institute of Singapore, Agency for Science Technology and Research)

  • Mary Tsikitis

    (Biomedical Research Foundation of the Academy of Athens)

  • Georgios Kazamias

    (Evangelismos General Hospital)

  • Konstantinos Potaris

    (Sotiria General Hospital)

  • Georgios T. Stathopoulos

    (University of Patras, Rio
    Ludwig-Maximilians University and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL))

  • Spyros Zakynthinos

    (National and Kapodistrian University of Athens)

  • Ioannis Kalomenidis

    (National and Kapodistrian University of Athens)

  • Vassili Soumelis

    (Integrative Biology of Human Dendritic Cells and T Cells, Institute Curie)

  • George Kollias

    (Biomedical Sciences Research Center Alexander Fleming
    National and Kapodistrian University of Athens)

  • Maria Tsoumakidou

    (Biomedical Sciences Research Center Alexander Fleming)

Abstract

Lung adenocarcinoma (LUAD)-derived Wnts increase cancer cell proliferative/stemness potential, but whether they impact the immune microenvironment is unknown. Here we show that LUAD cells use paracrine Wnt1 signaling to induce immune resistance. In TCGA, Wnt1 correlates strongly with tolerogenic genes. In another LUAD cohort, Wnt1 inversely associates with T cell abundance. Altering Wnt1 expression profoundly affects growth of murine lung adenocarcinomas and this is dependent on conventional dendritic cells (cDCs) and T cells. Mechanistically, Wnt1 leads to transcriptional silencing of CC/CXC chemokines in cDCs, T cell exclusion and cross-tolerance. Wnt-target genes are up-regulated in human intratumoral cDCs and decrease upon silencing Wnt1, accompanied by enhanced T cell cytotoxicity. siWnt1-nanoparticles given as single therapy or part of combinatorial immunotherapies act at both arms of the cancer-immune ecosystem to halt tumor growth. Collectively, our studies show that Wnt1 induces immunologically cold tumors through cDCs and highlight its immunotherapeutic targeting.

Suggested Citation

  • Dimitra Kerdidani & Panagiotis Chouvardas & Ares Rocanin Arjo & Ioanna Giopanou & Giannoula Ntaliarda & Yu Amanda Guo & Mary Tsikitis & Georgios Kazamias & Konstantinos Potaris & Georgios T. Stathopou, 2019. "Wnt1 silences chemokine genes in dendritic cells and induces adaptive immune resistance in lung adenocarcinoma," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09370-z
    DOI: 10.1038/s41467-019-09370-z
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