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

Dimitra Kerdidani, Panagiotis Chouvardas, Ares Rocanin Arjo, Ioanna Giopanou, Giannoula Ntaliarda, Yu Amanda Guo, Mary Tsikitis, Georgios Kazamias, Konstantinos Potaris, Georgios T. Stathopoulos, Spyros Zakynthinos, Ioannis Kalomenidis, Vassili Soumelis, George Kollias and Maria Tsoumakidou ()
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Dimitra Kerdidani: Biomedical Sciences Research Center Alexander Fleming
Panagiotis Chouvardas: Biomedical Sciences Research Center Alexander Fleming
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
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
Maria Tsoumakidou: Biomedical Sciences Research Center Alexander Fleming

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09370-z

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