Hepatobiliary cancer comprises a heterogeneous group of malignancies in which the standard treatments for advanced disease are minimally effective and evolve slowly over time. Like the majority of gastrointestinal cancers, with some notable exceptions, the impact of immune-based approaches is yet to be experienced. Notwithstanding this, the etiological background of hepatobiliary cancer - overlapping in almost every known causative or associated factor with inflammation - provides a strong clue that these approaches may have an impact on this group of diseases. This review seeks to put the management of hepatobiliary cancers in the context of its inflammation-based etiology, with the aim of pointing to the therapeutic opportunities in immune-based approaches currently entering the clinic or those that are about to do so.

Keywords:
Immune, Inflammation, Immune-evasion, Hepatobiliary, Cholangiocarcinoma
1.
Nogueira L, Foerster C, Groopman J, et al: Association of aflatoxin with gallbladder cancer in Chile. JAMA 2015;313:2075-2077.
2.
Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.
3.
Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010;362:1273-1281.
4.
Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411-422.
5.
Hodi FS, O'Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-223.
6.
Robert C, Thomas L, Bondarenko I, et al: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-2526.
7.
Brahmer JR, Tykodi SS, Chow LQ, et al: Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-2465.
8.
Topalian SL, Hodi FS, Brahmer JR, et al: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454.
9.
Chung KY, Gore I, Fong L, et al: Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Oncol 2010;28:3485-3490.
10.
Royal RE, Levy C, Turner K, et al: Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother 2010;33:828-833.
11.
Jiang Y, Li Y, Zhu B: T-cell exhaustion in the tumor microenvironment. Cell Death Dis 2015;6:e1792.
12.
Trinchieri G: Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol 2012;30:677-706.
13.
Rizvi S, Gores GJ: Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 2013;145:1215-1229.
14.
Chang JS, Tsai CR, Chen LT: Medical risk factors associated with cholangiocarcinoma in Taiwan: a population-based case-control study. PLoS One 2013;8:e69981.
15.
El-Serag HB, Engels EA, Landgren O, et al: Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: a population-based study of U.S. veterans. Hepatology 2009;49:116-123.
16.
Mizukoshi E, Nakamoto Y, Arai K, et al: Comparative analysis of various tumor-associated antigen-specific t-cell responses in patients with hepatocellular carcinoma. Hepatology 2011;53:1206-1216.
17.
Korangy F, Ormandy LA, Bleck JS, et al: Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in hepatocellular carcinoma. Clin Cancer Res 2004;10:4332-4341.
18.
Fu J, Xu D, Liu Z, et al: Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007;132:2328-2339.
19.
Gao Q, Qiu SJ, Fan J, et al: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007;25:2586-2593.
20.
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;344:641-645.
21.
Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA Jr, Kinzler KW: Cancer genome landscapes. Science 2013;339:1546-1558.
22.
Nakamura H, Arai Y, Totoki Y, et al: Genomic spectra of biliary tract cancer. Nat Genet 2015;47:1003-1010.
23.
Tran E, Ahmadzadeh M, Lu YC, et al: Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 2015;350:1387-1390.
24.
Garnelo M, Tan A, Her Z, et al: Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 2017;66:342-351.
25.
Chew V, Tow C, Teo M, et al: Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. J Hepatol 2010;52:370-379.
26.
Sabbatino F, Villani V, Yearley JH, et al: PD-L1 and HLA class I antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma. Clin Cancer Res 2016;22:470-478.
27.
Nakakubo Y, Miyamoto M, Cho Y, et al: Clinical significance of immune cell infiltration within gallbladder cancer. Br J Cancer 2003;89:1736-1742.
28.
Goeppert B, Frauenschuh L, Zucknick M, et al: Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br J Cancer 2013;109:2665-2674.
29.
Zhuo C, Xu Y, Ying M, et al: FOXP3+ Tregs: heterogeneous phenotypes and conflicting impacts on survival outcomes in patients with colorectal cancer. Immunol Res 2015;61:338-347.
30.
Campoli M, Ferrone S: HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene 2008;27:5869-5885.
31.
Campoli M, Ferrone S: Tumor escape mechanisms: potential role of soluble HLA antigens and NK cells activating ligands. Tissue Antigens 2008;72:321-334.
32.
Ryschich E, Nötzel T, Hinz U, et al: Control of T-cell-mediated immune response by HLA class I in human pancreatic carcinoma. Clin Cancer Res 2005;11(2 pt 1):498-504.
33.
Fujiwara K, Higashi T, Nouso K, et al: Decreased expression of B7 costimulatory molecules and major histocompatibility complex class-I in human hepatocellular carcinoma. J Gastroenterol Hepatol 2004;19:1121-1127.
34.
Goeppert B, Frauenschuh L, Zucknick M, et al: Major histocompatibility complex class I expression impacts on patient survival and type and density of immune cells in biliary tract cancer. Br J Cancer 2015;113:1343-1349.
35.
Greten TF, Duffy AG, Korangy F: Hepatocellular carcinoma from an immunologic perspective. Clin Cancer Res 2013;19:6678-6685.
36.
Xu XD, Hu J, Wang M, et al: Circulating myeloid-derived suppressor cells in patients with pancreatic cancer. Hepatobiliary Pancreat Dis Int 2016;15:99-105.
37.
Gao Q, Wang XY, Qiu SJ, et al: Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009;15:971-979.
38.
Zeng Z, Shi F, Zhou L, et al: Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma. PLoS One 2011;6:e23621.
39.
Ye Y, Zhou L, Xie X, Jiang G, Xie H, Zheng S: 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;100:500-504.
40.
Kirn DH, Thorne SH: Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat Rev Cancer 2009;9:64-71.
41.
Park BH, Hwang T, Liu TC, et al: Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncol 2008;9:533-542.
42.
Heo J, Reid T, Ruo L, et al: Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat Med 2013;19:329-336.
43.
Sangro B, Gomez-Martin C, de la Mata M, et al: A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol 2013;59:81-88.
44.
El-Khoueiry AB, Melero I, Crocenzi TS, et al: Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 2015;33:LBA101.
45.
Greten TF, Korangy F: Radiofrequency ablation for the treatment of HCC-maybe much more than simple tumor destruction? J Hepatol 2010;53:775-776.
46.
den Brok MH, Sutmuller RP, Nierkens S, et al: Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity. Br J Cancer 2006;95:896-905.
47.
Zerbini A, Pilli M, Penna A, et al: Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses. Cancer Res 2006;66:1139-1146.
48.
Zerbini A, Pilli M, Fagnoni F, et al: Increased immunostimulatory activity conferred to antigen-presenting cells by exposure to antigen extract from hepatocellular carcinoma after radiofrequency thermal ablation. J Immunother 2008;31:271-282.
49.
Hansler J, Wissniowski TT, Schuppan D, et al: Activation and dramatically increased cytolytic activity of tumor specific T lymphocytes after radio-frequency ablation in patients with hepatocellular carcinoma and colorectal liver metastases. World J Gastroenterol 2006;12:3716-3721.
50.
Hiroishi K, Eguchi J, Baba T, et al: Strong CD8(+) T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J Gastroenterol 2010;45:451-458.
51.
Johnson EE, Yamane BH, Buhtoiarov IN, et al: Radiofrequency ablation combined with KS-IL2 immunocytokine (EMD 273066) results in an enhanced antitumor effect against murine colon adenocarcinoma. Clin Cancer Res 2009;15:4875-4884.
52.
Nijkamp MW, Borren A, Govaert KM, et al: Radiofrequency ablation of colorectal liver metastases induces an inflammatory response in distant hepatic metastases but not in local accelerated outgrowth. J Surg Oncol 2010;101:551-556.
53.
Duffy AG, Makarova-Rusher OV, Kerkar SP, et al: A pilot study of tremelimumab - a monoclonal antibody against CTLA-4 - in combination with either trans catheter arterial chemoembolization (TACE) or radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC). J Clin Oncol 2015;33:4081.
54.
Kaida M, Morita-Hoshi Y, Soeda A, et al: Phase 1 trial of Wilms tumor 1 (WT1) peptide vaccine and gemcitabine combination therapy in patients with advanced pancreatic or biliary tract cancer. J Immunother 2011;34:92-99.
55.
Yamamoto K, Ueno T, Kawaoka T, et al: MUC1 peptide vaccination in patients with advanced pancreas or biliary tract cancer. Anticancer Res 2005;25:3575-3579.
56.
Aruga A, Takeshita N, Kotera Y, et al: Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer. J Transl Med 2014;12:61.
57.
Kobayashi M, Sakabe T, Abe H, et al: Dendritic cell-based immunotherapy targeting synthesized peptides for advanced biliary tract cancer. J Gastrointest Surg 2013;17:1609-1617.
58.
Lepisto AJ, Moser AJ, Zeh H, et al: A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther 2008;6:955-964.
59.
Shimomura A, Fujiwara Y, Kondo S, et al: Tremelimumab-associated tumor regression following after initial progression: two case reports. Immunotherapy 2016;8:9-15.
60.
Bang YJ, Doi T, De Braud F, Piha-Paul S, Hollebecque A, Abdul Razak AR, Lin CC, Ott PA, He AR, Yuan SS, Koshiji M, Lam B, Aggarwal R: Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: Interim results of KEYNOTE-028. Eur J Cancer 2015;51(suppl 3):S112.
61.
Duffy AG, Greten TF: Immunological off-target effects of standard treatments in gastrointestinal cancers. Ann Oncol 2014;25:24-32.
62.
Liu WM, Fowler DW, Smith P, Dalgleish AG: Pre-treatment with chemotherapy can enhance the antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br J Cancer 2010;102:115-123.
63.
Burris H, Storniolo AM: Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil. Eur J Cancer 1997;33(suppl 1):S18-S22.
64.
Koido S, Kan S, Yoshida K, et al: Immunogenic modulation of cholangiocarcinoma cells by chemoimmunotherapy. Anticancer Res 2014;34:6353-6361.
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2017
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