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, Maria Tsoumakidou
Author Information
Dimitra Kerdidani: Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari-Athens, 16672, Greece. ORCID
Panagiotis Chouvardas: Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari-Athens, 16672, Greece. ORCID
Ares Rocanin Arjo: Integrative Biology of Human Dendritic Cells and T Cells, Institute Curie, Paris, 75005, France.
Ioanna Giopanou: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Achaia, 26504, Greece. ORCID
Giannoula Ntaliarda: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Achaia, 26504, Greece.
Yu Amanda Guo: Computational and Systems Biology, Genome Institute of Singapore, Agency for Science Technology and Research, Singapore, 138672, Singapore.
Mary Tsikitis: Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece. ORCID
Georgios Kazamias: Department of Histopathology, Evangelismos General Hospital, Athens, 10676, Greece. ORCID
Konstantinos Potaris: Department of Thoracic Surgery, Sotiria General Hospital, Athens, 11527, Greece.
Georgios T Stathopoulos: Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Achaia, 26504, Greece. ORCID
Spyros Zakynthinos: 1st Department of Critical Care and Pulmonary Medicine, Medical School, National and Kapodistrian University of Athens, Athens, 10676, Greece.
Ioannis Kalomenidis: 1st Department of Critical Care and Pulmonary Medicine, Medical School, National and Kapodistrian University of Athens, Athens, 10676, Greece. ORCID
Vassili Soumelis: Integrative Biology of Human Dendritic Cells and T Cells, Institute Curie, Paris, 75005, France. ORCID
George Kollias: Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari-Athens, 16672, Greece. ORCID
Maria Tsoumakidou: Division of Immunology, Biomedical Sciences Research Center Alexander Fleming, Vari-Athens, 16672, Greece. tsoumakidou@fleming.gr. ORCID
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.
