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DKK1 drives immune suppressive phenotypes in intrahepatic cholangiocarcinoma and can be targeted with anti-DKK1 therapeutic DKN-01.
Jarman, Edward J; Horcas-Lopez, Marta; Waddell, Scott H; MacMaster, Stephanie; Gournopanos, Konstantinos; Soong, Daniel Y H; Musialik, Kamila I; Tsokkou, Panagiota; Ng, Minn-E; Cambridge, William A; Wilson, David H; Kagey, Michael H; Newman, Walter; Pollard, Jeffrey W; Boulter, Luke.
Afiliación
  • Jarman EJ; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Horcas-Lopez M; MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
  • Waddell SH; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • MacMaster S; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Gournopanos K; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Soong DYH; MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
  • Musialik KI; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Tsokkou P; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Ng ME; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Cambridge WA; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Wilson DH; Department of Clinical Surgery, University of Edinburgh, Little France Crescent, Edinburgh, UK.
  • Kagey MH; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Newman W; Leap Therapeutics, Cambridge, Massachusetts, USA.
  • Pollard JW; Leap Therapeutics, Cambridge, Massachusetts, USA.
  • Boulter L; MRC Centre for Reproductive Health, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
Liver Int ; 43(1): 208-220, 2023 01.
Article en En | MEDLINE | ID: mdl-35924447
BACKGROUND AND AIMS: Dickkopf-1 (DKK1) is associated with poor prognosis in intrahepatic cholangiocarcinoma (iCCA), but the mechanisms behind this are unclear. Here, we show that DKK1 plays an immune regulatory role in vivo and inhibition reduces tumour growth. METHODS: Various in vivo GEMM mouse models and patient samples were utilized to assess the effects of tumour specific DKK1 overexpression in iCCA. DKK1-driven changes to the tumour immune microenvironment were characterized by immunostaining and gene expression analysis. DKK1 overexpressing and damage-induced models of iCCA were used to demonstrate the therapeutic efficacy of DKK1 inhibition in these contexts using the anti-DKK1 therapeutic, DKN-01. RESULTS: DKK1 overexpression in mouse models of iCCA drives an increase in chemokine and cytokine signalling, the recruitment of regulatory macrophages, and promotes the formation of a tolerogenic niche with higher numbers of regulatory T cells. We show a similar association of DKK1 with FOXP3 and regulatory T cells in patient tissue and gene expression data, demonstrating these effects are relevant to human iCCA. Finally, we demonstrate that inhibition of DKK1 with the monoclonal antibody mDKN-01 is effective at reducing tumour burden in two distinct mouse models of the disease. CONCLUSION: DKK1 promotes tumour immune evasion in iCCA through the recruitment of immune suppressive macrophages. Targeting DKK1 with a neutralizing antibody is effective at reducing tumour growth in vivo. As such, DKK1 targeted and immune modulatory therapies may be an effective strategy in iCCA patients with high DKK1 tumour expression or tolerogenic immune phenotypes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de los Conductos Biliares / Colangiocarcinoma / Péptidos y Proteínas de Señalización Intercelular Límite: Animals / Humans Idioma: En Revista: Liver Int Asunto de la revista: GASTROENTEROLOGIA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de los Conductos Biliares / Colangiocarcinoma / Péptidos y Proteínas de Señalización Intercelular Límite: Animals / Humans Idioma: En Revista: Liver Int Asunto de la revista: GASTROENTEROLOGIA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos