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Nat Commun. 2019 Mar 29;10(1):1405. doi: 10.1038/s41467-019-09370-z.

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

Author information

1
Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari-Athens, 16672, Greece.
2
1st Department of Critical Care and Pulmonary Medicine, Medical School, National and Kapodistrian University of Athens, Athens, 10676, Greece.
3
Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, 3012, Switzerland.
4
Department for BioMedical Research, University of Bern, Bern, 3012, Switzerland.
5
Integrative Biology of Human Dendritic Cells and T Cells, Institute Curie, Paris, 75005, France.
6
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Achaia, 26504, Greece.
7
Computational and Systems Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, 138672, Singapore.
8
Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece.
9
Department of Histopathology, Evangelismos General Hospital, Athens, 10676, Greece.
10
Department of Thoracic Surgery, Sotiria General Hospital, Athens, 11527, Greece.
11
Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Ludwig-Maximilians University and Helmholtz Center Munich, Member of the German Center for Lung Research (DZL), Munich, Bavaria, 81377, Germany.
12
Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, 11527, Greece.
13
Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari-Athens, 16672, Greece. tsoumakidou@fleming.gr.

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.

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