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

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          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.

          Abstract

          The Wnt pathway regulates anti-tumour immunity in melanoma. Here, the authors show that, in lung adenocarcinoma, secretion of the ligand Wnt1 induces immune resistance by impairing the ability of dendritic cells to cross-prime T cells, and that blocking Wnt signalling enhances rejection of tumours by acting both on the cancer and immune cells.

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          Most cited references42

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          Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition.

          Large numbers of melanoma lesions develop resistance to targeted inhibition of mutant BRAF or fail to respond to checkpoint blockade. We explored whether modulation of intratumoral antigen-presenting cells (APCs) could increase responses to these therapies. Using mouse melanoma models, we found that CD103(+) dendritic cells (DCs) were the only APCs transporting intact antigens to the lymph nodes and priming tumor-specific CD8(+) T cells. CD103(+) DCs were required to promote anti-tumoral effects upon blockade of the checkpoint ligand PD-L1; however, PD-L1 inhibition only led to partial responses. Systemic administration of the growth factor FLT3L followed by intratumoral poly I:C injections expanded and activated CD103(+) DC progenitors in the tumor, enhancing responses to BRAF and PD-L1 blockade and protecting mice from tumor rechallenge. Thus, the paucity of activated CD103(+) DCs in tumors limits checkpoint-blockade efficacy and combined FLT3L and poly I:C therapy can enhance tumor responses to checkpoint and BRAF blockade.
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            Overcoming cellular barriers for RNA therapeutics

            Recent progress in delivering RNA therapeutics to the inside of cells might lead to more success in clinical applications.
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              Wnt signaling pathway in non-small cell lung cancer.

              D Stewart (2014)
              Wnt/β-catenin alterations are prominent in human malignancies. In non-small cell lung cancer (NSCLC), β-catenin and APC mutations are uncommon, but Wnt signaling is important in NSCLC cell lines, and Wnt inhibition reduces proliferation. Overexpression of Wnt-1, -2, -3, and -5a and of Wnt-pathway components Frizzled-8, Dishevelled, Porcupine, and TCF-4 is common in resected NSCLC and is associated with poor prognosis. Conversely, noncanonical Wnt-7a suppresses NSCLC development and is often downregulated. Although β-catenin is often expressed in NSCLCs, it was paradoxically associated with improved prognosis in some series, possibly because of E-cadherin interactions. Downregulation of Wnt inhibitors (eg, by hypermethylation) is common in NSCLC tumor cell lines and resected samples; may be associated with high stage, dedifferentiation, and poor prognosis; and has been reported for AXIN, sFRPs 1-5, WIF-1, Dkk-1, Dkk-3, HDPR1, RUNX3, APC, CDX2, DACT2, TMEM88, Chibby, NKD1, EMX2, ING4, and miR-487b. AXIN is also destabilized by tankyrases, and GSK3β may be inactivated through phosphorylation by EGFR. Preclinically, restoration of Wnt inhibitor function is associated with reduced Wnt signaling, decreased cell proliferation, and increased apoptosis. Wnt signaling may also augment resistance to cisplatin, docetaxel, and radiotherapy, and Wnt inhibitors may restore sensitivity. Overall, available data indicate that Wnt signaling substantially impacts NSCLC tumorigenesis, prognosis, and resistance to therapy, with loss of Wnt signaling inhibitors by promoter hypermethylation or other mechanisms appearing to be particularly important. Wnt pathway antagonists warrant exploration clinically in NSCLC. Agents blocking selected specific β-catenin interactions and approaches to increase expression of downregulated Wnt inhibitors may be of particular interest.
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                Author and article information

                Contributors
                tsoumakidou@fleming.gr
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                29 March 2019
                29 March 2019
                2019
                : 10
                : 1405
                Affiliations
                [1 ]ISNI 0000 0004 0635 706X, GRID grid.424165.0, Division of Immunology, , Biomedical Sciences Research Center Alexander Fleming, ; Vari-Athens, 16672 Greece
                [2 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, 1st Department of Critical Care and Pulmonary Medicine, Medical School, , National and Kapodistrian University of Athens, ; Athens, 10676 Greece
                [3 ]ISNI 0000 0001 0726 5157, GRID grid.5734.5, Department of Medical Oncology, Inselspital, Bern University Hospital, , University of Bern, ; Bern, 3012 Switzerland
                [4 ]ISNI 0000 0001 0726 5157, GRID grid.5734.5, Department for BioMedical Research, , University of Bern, ; Bern, 3012 Switzerland
                [5 ]ISNI 0000 0004 0639 6384, GRID grid.418596.7, Integrative Biology of Human Dendritic Cells and T Cells, Institute Curie, ; Paris, 75005 France
                [6 ]ISNI 0000 0004 0576 5395, GRID grid.11047.33, Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, , University of Patras, Rio, ; Achaia, 26504 Greece
                [7 ]ISNI 0000 0004 0620 715X, GRID grid.418377.e, Computational and Systems Biology, , Genome Institute of Singapore, Agency for Science Technology and Research, ; Singapore, 138672 Singapore
                [8 ]ISNI 0000 0004 0620 8857, GRID grid.417975.9, Center of Basic Research, , Biomedical Research Foundation of the Academy of Athens, ; Athens, 11527 Greece
                [9 ]ISNI 0000 0004 4670 4329, GRID grid.414655.7, Department of Histopathology, , Evangelismos General Hospital, ; Athens, 10676 Greece
                [10 ]GRID grid.416145.3, Department of Thoracic Surgery, , Sotiria General Hospital, ; Athens, 11527 Greece
                [11 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, 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 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, Department of Physiology, Medical School, , National and Kapodistrian University of Athens, ; Athens, 11527 Greece
                Author information
                http://orcid.org/0000-0001-8681-693X
                http://orcid.org/0000-0003-1527-3151
                http://orcid.org/0000-0003-4393-7517
                http://orcid.org/0000-0002-6929-6239
                http://orcid.org/0000-0003-4071-4182
                http://orcid.org/0000-0002-9215-6461
                http://orcid.org/0000-0001-9729-3492
                http://orcid.org/0000-0003-1849-9834
                http://orcid.org/0000-0003-1867-3150
                http://orcid.org/0000-0001-7959-4793
                Article
                9370
                10.1038/s41467-019-09370-z
                6441097
                30926812
                c174bdc1-f431-47e9-b941-0b73a5baea1f
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 15 May 2018
                : 5 March 2019
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