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Review

Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy

&
Pages 429-438 | Received 10 Jul 2020, Accepted 14 Dec 2020, Published online: 28 Dec 2020

References

  • Rizvi S, Khan SA, Hallemeier CL, et al. Cholangiocarcinoma - evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018 Feb;15(2):95–111.
  • Banales JM, Marin JJG, Lamarca A, et al. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat Rev Gastroenterol Hepatol. 2020 Sep;17(9):557–588.
  • Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010 Apr 8;362(14):1273–1281.
  • Jin M-Z, Jin W-L. The updated landscape of tumor microenvironment and drug repurposing. Signal Transduct Target Ther. 2020 [ Cited 2020 25 Aug];5(1):166.
  • Hogdall D, Lewinska M, Andersen JB. Desmoplastic tumor microenvironment and immunotherapy in cholangiocarcinoma. Trends Cancer. 2018 Mar;4(3):239–255.
  • Dou L, Shi X, He X, et al. macrophage phenotype and function in liver disorder. Front Immunol. 2019;10:3112.
  • Cassetta L, Fragkogianni S, Sims AH, et al. human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell. 2019 Apr 15;35(4):588–602. e10.
  • Yuan D, Huang S, Berger E, et al. Kupffer cell-derived tnf triggers cholangiocellular tumorigenesis through jnk due to chronic mitochondrial dysfunction and ROS. Cancer Cell. 2017 Jun 12;31(6):771–789. e6.
  • Sun D, Luo T, Dong P, et al. CD86(+)/CD206(+) tumor-associated macrophages predict prognosis of patients with intrahepatic cholangiocarcinoma. PeerJ. 2020;8:e8458.
  • Kitano Y, Okabe H, Yamashita YI, et al. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br J Cancer. 2018 Jan;118(2):171–180.
  • Mitchem JB, Brennan DJ, Knolhoff BL, et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013 Feb 1;73(3):1128–1141.
  • Techasen A, Loilome W, Namwat N, et al. Cytokines released from activated human macrophages induce epithelial mesenchymal transition markers of cholangiocarcinoma cells. Asian Pac J Cancer Prev. 2012;13(Suppl):115–118.
  • Hasita H, Komohara Y, Okabe H, et al. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 2010 Aug;101(8):1913–1919.
  • Boulter L, Guest RV, Kendall TJ, et al. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J Clin Invest. 2015;125(3):1269–1285.
  • Cassetta L, Pollard JW. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov. 2018 Dec;17(12):887–904.
  • Loeuillard E, Yang J, Buckarma E, et al. Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma. J Clin Invest. 2020 Oct 01;130(10):5380–5396.
  • Matlung HL, Szilagyi K, Barclay NA, et al. The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol Rev. 2017 Mar;276(1):145–164.
  • Weiskopf K, Jahchan NS, Schnorr PJ, et al. CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer. J Clin Invest. 2016 Jul 1;126(7):2610–2620.
  • Willingham SB, Volkmer JP, Gentles AJ, et al. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662–6667.
  • Liu J, Xavy S, Mihardja S, et al. Targeting macrophage checkpoint inhibitor SIRPa for anticancer therapy. JCI Insight. 2020 May;;5(12):e134728.
  • Vaeteewoottacharn K, Kariya R, Pothipan P, et al. Attenuation of CD47-sirpalpha signal in cholangiocarcinoma potentiates tumor-associated macrophage-mediated phagocytosis and suppresses intrahepatic metastasis. Transl Oncol. 2019 Feb;12(2):217–225.
  • Cai B, Dongiovanni P, Corey KE, et al. Macrophage MerTK promotes liver fibrosis in nonalcoholic steatohepatitis. Cell Metab. 2020 Feb 4;31(2):406–421. e7.
  • Zhou Y, Fei M, Zhang G, et al. Blockade of the phagocytic receptor mertk on tumor-associated macrophages enhances P2X7R-dependent STING activation by tumor-derived cGAMP. Immunity. 2020 Feb 18;52(2):357–373. e9.
  • Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017 Jan;5(1):3–8.
  • Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age.Nat Immunol. 2018 [ Cited 2018 Feb 01];19(2):108–119.
  • Mazzoni A, Bronte V, Visintin A, et al. Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism. J Immunol. 2002 Jan 15;168(2):689–695.
  • Siret C, Collignon A, Silvy F, et al. Deciphering the crosstalk between myeloid-derived suppressor cells and regulatory t cells in pancreatic ductal adenocarcinoma. Front Immunol. 2020;10:3070.
  • Beury DW, Parker KH, Nyandjo M, et al. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors. J Leukoc Biol. 2014;96(6):1109–1118.
  • Xu XD, Hu J, Wang M, et al. Circulating myeloid-derived suppressor cells in patients with pancreatic cancer. Hbpd Int. 2016 Feb;15(1):99–105.
  • Ilkovitch D, Lopez DM. The liver is a site for tumor-induced myeloid-derived suppressor cell accumulation and immunosuppression. Cancer Res. 2009 Jul 1;69(13):5514–5521.
  • Lacotte S, Slits F, Orci LA, et al. Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma. Oncoimmunology. 2016;5(11):e1234565.
  • Stromnes IM, Brockenbrough JS, Izeradjene K, et al. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut. 2014 Nov;63(11):1769–1781.
  • Tavazoie MF, Pollack I, Tanqueco R, et al. LXR/ApoE activation restricts innate immune suppression in cancer. Cell. 2018;172(4):825–840. e18.
  • Guo D, Reinitz F, Youssef M, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 2011 Oct;1(5):442–456.
  • Pencheva N, Buss Colin G, Posada J, et al. Broad-Spectrum Therapeutic Suppression of Metastatic Melanoma through Nuclear Hormone Receptor Activation. Cell. 2014 Feb;156(5):986–1001
  • Wculek SK, Cueto FJ, Mujal AM, et al. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020 Jan;20(1):7–24.
  • Tran Janco JM, Lamichhane P, Karyampudi L, et al. Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol. 2015;194(7):2985–2991.
  • Takagi S, Miyagawa S, Ichikawa E, et al. Dendritic cells, T-cell infiltration, and Grp94 expression in cholangiocellular carcinoma. Hum Pathol. 2004 Jul;35(7):881–886.
  • Platzer B, Elpek Kutlu G, Cremasco V, et al. IgE/FcεRI-mediated antigen cross-presentation by dendritic cells enhances anti-tumor immune responses. Cell Rep. 2015;10(9):1487–1495.
  • Martín-Sierra C, Martins R, Laranjeira P, et al. Functional impairment of circulating FcεRI(+) Monocytes and myeloid dendritic cells in hepatocellular carcinoma and cholangiocarcinoma patients. Cytometry B Clin Cytom. 2019 Nov;96(6):490–495.
  • Hegde S, Krisnawan VE, Herzog BH, et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell. 2020 Mar 16;37(3):289–307. e9.
  • Freedman RS, Vadhan-Raj S, Butts C, et al. Pilot study of Flt3 ligand comparing intraperitoneal with subcutaneous routes on hematologic and immunologic responses in patients with peritoneal carcinomatosis and mesotheliomas. Clin Cancer Res off J Am Assoc Cancer Res. 2003 Nov 1;9(14):5228–5237.
  • Morse MA, Nair S, Fernandez-Casal M, et al. Preoperative mobilization of circulating dendritic cells by Flt3 ligand administration to patients with metastatic colon cancer. J Clin Oncol. 2000 Dec 1;18(23):3883–3893.
  • Vonderheide RH. CD40 Agonist antibodies in cancer immunotherapy. Annu Rev Med. 2020 Jan 27;71(1):47–58.
  • Borges L, Miller RE, Jones J, et al. Synergistic action of fms-like tyrosine kinase 3 ligand and CD40 ligand in the induction of dendritic cells and generation of antitumor immunity in vivo. J Immunol. 1999 Aug 1;163(3):1289–1297.
  • Mandal A, Viswanathan C. Natural killer cells: in health and disease. Hematol Oncol Stem Cell Ther. 2015 Jun;8(2):47–55.
  • Chiossone L, Dumas PY, Vienne M, et al. Natural killer cells and other innate lymphoid cells in cancer. Nat Rev Immunol. 2018 Nov;18(11):671–688.
  • Peng L, Zhang J, Teng Y-S, et al. Tumor-associated monocytes/macrophages impair NK-cell function via TGFβ1 in human gastric cancer. Cancer Immunol Res. 2017;5(3):248–256.
  • Jun E, Song AY, Choi J-W, et al. Progressive impairment of NK cell cytotoxic degranulation is associated with TGF-β1 deregulation and disease progression in pancreatic cancer. Front Immunol. 2019;10:1354.
  • Zheng X, Qian Y, Fu B, et al. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol. 2019 Dec;20(12):1656–1667.
  • Melum E, Karlsen TH, Schrumpf E, et al. Cholangiocarcinoma in primary sclerosing cholangitis is associated with NKG2D polymorphisms. Hepatology. 2008 Jan;47(1):90–96.
  • Wadsworth CA, Dixon PH, Taylor-Robinson S, et al. Polymorphisms in natural killer cell receptor protein 2D (NKG2D) as a risk factor for cholangiocarcinoma. J Clin Exp Hepatol. 2019 Mar-Apr;9(2):171–175.
  • Tsukagoshi M, Wada S, Yokobori T, et al. Overexpression of natural killer group 2 member D ligands predicts favorable prognosis in cholangiocarcinoma. Cancer Sci. 2016 Feb;107(2):116–122.
  • Cornillet M, Jansson H, Schaffer M, et al. Imbalance of genes encoding natural killer immunoglobulin-like receptors and human leukocyte antigen in patients with biliary cancer. Gastroenterology. 2019 Oct;157(4):1067–1080. e9.
  • Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014 May 9;344(6184):641–645.
  • Goeppert B, Frauenschuh L, Zucknick M, et al. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer. 2013 Nov 12;109(10):2665–2674.
  • Oshikiri T, Miyamoto M, Shichinohe T, et al. Prognostic value of intratumoral CD8+ T lymphocyte in extrahepatic bile duct carcinoma as essential immune response. J Surg Oncol. 2003 Dec;84(4):224–228.
  • Ma C, Peng C, Lu X, et al. Downregulation of FOXP3 inhibits invasion and immune escape in cholangiocarcinoma. Biochem Biophys Res Commun. 2015 Mar 6;458(2):234–239.
  • Wang X, Li X, Wei X, et al. PD-L1 is a direct target of cancer-FOXP3 in pancreatic ductal adenocarcinoma (PDAC), and combined immunotherapy with antibodies against PD-L1 and CCL5 is effective in the treatment of PDAC. Signal Transduct Target Ther. 2020 Apr 17;5(1):38.
  • Walter D, Herrmann E, Schnitzbauer AA, et al. PD-L1 expression in extrahepatic cholangiocarcinoma. Histopathology. 2017 Sep;71(3):383–392.
  • Wang L, Dong H, Ni S, et al. Programmed death-ligand 1 is upregulated in intrahepatic lymphoepithelioma-like cholangiocarcinoma. Oncotarget. 2016 Oct 25;7(43):69749–69759.
  • Ye Y, Zhou L, Xie X, et al. Interaction of B7-H1 on intrahepatic cholangiocarcinoma cells with PD-1 on tumor-infiltrating T cells as a mechanism of immune evasion. J Surg Oncol. 2009 Nov 1;100(6):500–504.
  • Mody K, Starr J, Saul M, et al. Patterns and genomic correlates of PD-L1 expression in patients with biliary tract cancers. J Gastrointest Oncol. 2019 Dec;10(6):1099–1109.
  • Kang J, Yoo C, Jeong JH, et al. Efficacy and safety of pembrolizumab in patients with PD-L1 positive advanced biliary tract cancer (BTC): A prospective cohort study. J clin oncol. 2019;37(15_suppl):4082.
  • Lim YJ, Koh J, Kim K, et al. Clinical implications of Cytotoxic T Lymphocyte Antigen-4 expression on tumor cells and tumor-infiltrating lymphocytes in extrahepatic bile duct cancer patients undergoing surgery plus adjuvant chemoradiotherapy. Target Oncol. 2017 Apr;12(2):211–218.
  • Zappasodi R, Sirard C, Li Y, et al. Rational design of anti-GITR-based combination immunotherapy. Nat Med. 2019 May;25(5):759–766.
  • Zhou G, Sprengers D, Mancham S, et al. Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules. J Hepatol. 2019 Oct;71(4):753–762.
  • Vaquero J, Aoudjehane L, Fouassier L. Cancer-associated fibroblasts in cholangiocarcinoma. Curr Opin Gastroenterol. 2020 Mar;36(2):63–69.
  • Itou RA, Uyama N, Hirota S, et al. Immunohistochemical characterization of cancer-associated fibroblasts at the primary sites and in the metastatic lymph nodes of human intrahepatic cholangiocarcinoma. Hum Pathol. 2019 Jan;83:77–89.
  • Zhang XF, Dong M, Pan YH, et al. Expression pattern of cancer-associated fibroblast and its clinical relevance in intrahepatic cholangiocarcinoma. Hum Pathol. 2017 Jul;65:92–100.
  • Sirica AE, Almenara JA, Li C. Periostin in intrahepatic cholangiocarcinoma: pathobiological insights and clinical implications. Exp Mol Pathol. 2014 Dec;97(3):515–524.
  • Manzanares M, Campbell DJW, Maldonado GT, et al. Overexpression of periostin and distinct mesothelin forms predict malignant progression in a rat cholangiocarcinoma model. Hepatol Commun. 2018 Feb;2(2):155–172.
  • Utispan K, Thuwajit P, Abiko Y, et al. Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker. Mol Cancer. 2010 Jan;24(9):13.
  • Mertens JC, Fingas CD, Christensen JD, et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res. 2013 Jan 15;73(2):897–907.
  • Cadamuro M, Brivio S, Mertens J, et al. Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma. J Hepatol. 2019;70(4):700–709.
  • Thongchot S, Ferraresi A, Vidoni C, et al. Resveratrol interrupts the pro-invasive communication between cancer associated fibroblasts and cholangiocarcinoma cells. Cancer Lett. 2018 Aug;28(430):160–171.
  • Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2071–82
  • Öztürk Akcora B, Storm G, Prakash J, et al. Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl(4)-induced liver fibrogenesis mouse model. Sci Rep-Uk. 2017;7(1):445.
  • Wollin L, Togbe D, Ryffel B. Effects of nintedanib in an animal model of liver fibrosis. Biomed Res Int. 2020;2020:3867198.
  • Gabasa M, Ikemori R, Hilberg F, et al. Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients. Br J Cancer. 2017 Oct 10;117(8):1128–1138.
  • Yamanaka T, Harimoto N, Yokobori T, et al. Nintedanib inhibits intrahepatic cholangiocarcinoma aggressiveness via suppression of cytokines extracted from activated cancer-associated fibroblasts. Br J Cancer. 2020 Feb;122(7):986–994
  • Herbeuval JP, Lelievre E, Lambert C, et al. Recruitment of STAT3 for production of IL-10 by colon carcinoma cells induced by macrophage-derived IL-6. J Immunol. 2004 Apr 1;172(7):4630–4636.
  • Cho H, Seo Y, Loke KM, et al. Cancer-stimulated CAFs enhance monocyte differentiation and protumoral TAM activation via IL6 and GM-CSF secretion. Clin Cancer Res off J Am Assoc Cancer Res. 2018 Nov 1;24(21):5407–5421.
  • Isomoto H, Mott JL, Kobayashi S, et al. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology. 2007 Jan;132(1):384–396.
  • Wehbe H, Henson R, Meng F, et al. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res. 2006 Nov 1;66(21):10517–10524.
  • Frampton G, Invernizzi P, Bernuzzi F, et al. Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism. Gut. 2012 Feb;61(2):268–277.
  • Yamada D, Rizvi S, Razumilava N, et al. IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism. Hepatology. 2015 May;61(5):1627–1642.
  • Sripa B, Thinkhamrop B, Mairiang E, et al. Elevated plasma IL-6 associates with increased risk of advanced fibrosis and cholangiocarcinoma in individuals infected by Opisthorchis viverrini. PLoS Negl Trop Dis. 2012;6(5):e1654.
  • Zhang M, Yang H, Wan L, et al. Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J Hepatol. 2020;73(5):1118–1130.
  • Ware MB, McQuinn C, Zaidi MY, et al. Dual blockade of IL-6 and CTLA-4 regresses pancreatic tumors in a CD4+ T cell-dependent manner. bioRxiv. 2020;2020(2):07.939199.
  • Kleinegger F, Hofer E, Wodlej C, et al. Pharmacologic IL-6Rα inhibition in cholangiocarcinoma promotes cancer cell growth and survival. Biochim Biophys Acta Mol Basis Dis. 2019 Feb 1;1865(2):308–321.
  • Lin Y, Li B, Yang X, et al. Fibroblastic FAP promotes intrahepatic cholangiocarcinoma growth via MDSCs recruitment. Neoplasia. 2019 Dec;21(12):1133–1142.
  • Eksteen B, Miles A, Curbishley SM, et al. Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10. J Immunol. 2006 Jul 1;177(1):593–603.
  • Fukuda Y, Asaoka T, Eguchi H, et al. Endogenous CXCL9 affects prognosis by regulating tumor-infiltrating natural killer cells in intrahepatic cholangiocarcinoma. Cancer Sci. 2020 Feb;111(2):323–333.
  • Fingas CD, Bronk SF, Werneburg NW, et al. Myofibroblast-derived PDGF-BB promotes hedgehog survival signaling in cholangiocarcinoma cells. Hepatology. 2011;54(6):2076–2088.
  • Cadamuro M, Nardo G, Indraccolo S, et al. Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology. 2013;58(3):1042–1053.
  • Clapéron A, Mergey M, Aoudjehane L, et al. Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor. Hepatology. 2013 Dec;58(6):2001–2011.
  • Vaeteewoottacharn K, Kariya R, Dana P, et al. Inhibition of carbonic anhydrase potentiates bevacizumab treatment in cholangiocarcinoma. Tumour Biol. 2016 Jul;37(7):9023–9035.
  • Yoshikawa D, Ojima H, Iwasaki M, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008 Jan 29;98(2):418–425.
  • Stacker SA, Caesar C, Baldwin ME, et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med. 2001 Feb;7(2):186–191.
  • Aishima S, Nishihara Y, Iguchi T, et al. Lymphatic spread is related to VEGF-C expression and D2-40-positive myofibroblasts in intrahepatic cholangiocarcinoma. Mod Pathol. 2008 Mar;21(3):256–264.
  • Ma L, Hernandez MO, Zhao Y, et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell. 2019 Oct 14;36(4):418–430. e6.
  • Yeh CN, Chang YC, Su Y, et al. Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients. Oncotarget. 2017 Dec 26;8(69):113444–113459.
  • Kim RD, Sanoff HK, Poklepovic AS, et al. A multi-institutional phase 2 trial of regorafenib in refractory advanced biliary tract cancer. Cancer. 2020 May 26; Aug 1;126(15):3464–3470
  • Shroff RT, Yarchoan M, O’Connor A, et al. The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma. Br J Cancer. 2017 May 23;116(11):1402–1407.
  • Kosaka N, Yoshioka Y, Fujita Y, et al. Versatile roles of extracellular vesicles in cancer. J Clin Invest. 2016 Apr 1;126(4):1163–1172.
  • Maas SLN, Breakefield XO, Weaver AM. Extracellular vesicles: unique intercellular delivery vehicles. Trends Cell Biol. 2017 Mar;27(3):172–188.
  • Becker A, Thakur BK, Weiss JM, et al. Extracellular vesicles in cancer: cell-to-cell mediators of metastasis. Cancer Cell. 2016 Dec 12;30(6):836–848.
  • Masyuk AI, Huang BQ, Ward CJ, et al. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am J Physiol Gastrointest Liver Physiol. 2010 Oct;299(4):G990–9.
  • Severino V, Dumonceau JM, Delhaye M, et al. Extracellular vesicles in bile as markers of malignant biliary stenoses. Gastroenterology. 2017 Aug;153(2):495–504 e8.
  • Li L, Masica D, Ishida M, et al. Human bile contains microRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis. Hepatology. 2014 Sep;60(3):896–907.
  • Arbelaiz A, Azkargorta M, Krawczyk M, et al. Serum extracellular vesicles contain protein biomarkers for primary sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2017 Oct;66(4):1125–1143.
  • Lapitz A, Arbelaiz A, O’Rourke CJ, et al. Patients with cholangiocarcinoma present specific rna profiles in serum and urine extracellular vesicles mirroring the tumor expression: novel liquid biopsy biomarkers for disease diagnosis. Cells. 2020 Mar 14;9(3):3.
  • Li L, Piontek K, Ishida M, et al. Extracellular vesicles carry microRNA-195 to intrahepatic cholangiocarcinoma and improve survival in a rat model. Hepatology. 2017 Feb;65(2):501–514.
  • Ota Y, Takahashi K, Otake S, et al. Extracellular vesicle-encapsulated miR-30e suppresses cholangiocarcinoma cell invasion and migration via inhibiting epithelial-mesenchymal transition. Oncotarget. 2018 Mar 27;9(23):16400–16417.
  • Piha-Paul SA, Oh D-Y, Ueno M, et al. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020;147(8):2190–2198.
  • Kim RD, Chung V, Alese OB, et al. A phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer. JAMA Oncol. 2020;6(6):888–894.
  • Klein O, Kee D, Nagrial A, et al. Evaluation of combination nivolumab and ipilimumab immunotherapy in patients with advanced biliary tract cancers: subgroup analysis of a phase 2 nonrandomized clinical trial. JAMA Oncol. 2020;6(9):1405–1409.
  • Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018 May;24(5):541–550.
  • Rizvi S, Fischbach SR, Bronk SF, et al. YAP-associated chromosomal instability and cholangiocarcinoma in mice. Oncotarget. 2018 Jan 19;9(5):5892–5905.
  • Neal JT, Li X, Zhu J, et al. Organoid modeling of the tumor immune microenvironment. Cell. 2018 Dec 13;175(7):1972–88. e16.

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