Top

Published in:

01-08-2019 | Cholangiocarcinoma | Original Article

Histopathology-based immunoscore predicts recurrence for intrahepatic cholangiocarcinoma after hepatectomy

Authors: Meng-Xin Tian, Yu-Fu Zhou, Wei-Feng Qu, Wei-Ren Liu, Lei Jin, Xi-Fei Jiang, Han Wang, Chen-Yang Tao, Pei-Yun Zhou, Yuan Fang, Zhen-Bin Ding, Yuan-Fei Peng, Jian Zhou, Jia Fan, Ying-Hong Shi

Published in: Cancer Immunology, Immunotherapy | Issue 8/2019

Abstract

Intrahepatic cholangiocarcinoma (ICC) is a rare malignancy with poor prognosis. The evaluation of recurrence risk after liver resection is of great importance for ICCs. We aimed to assess the prognostic value of intra- and peritumoral immune infiltrations and to establish a novel histopathology-related immunoscore (HRI) associated with ICC recurrence. A total of 280 ICC patients who received curative resection between February 2005 and July 2011 were enrolled in our study. Patients were randomly assigned to the derivation cohort (n = 176) or the validation cohort (n = 104). Sixteen immune biomarkers in both intra- and peritumoral tissues were examined by immunohistochemistry. The least absolute shrinkage and selection operator (LASSO) Cox model was used to establish the HRI score. Cox regression analysis was used for multivariate analysis. Nine recurrence-related immune features were identified and integrated into the HRI score. The HRI score was used to categorize patients into low-risk and high-risk groups using the X-tile software. Kaplan–Meier analysis presented that the HRI score showed good stratification between low-risk and high-risk groups in both the derivation cohort (P < 0.001) and the validation cohort (P = 0.014), respectively. Multivariate analysis demonstrated that serum γ-glutamyl transpeptidase, carbohydrate antigen 19-9, lymphoid metastasis, tumor numbers, and the HRI score were independent risk factors associated with recurrence-free survival (RFS). The combination of Shen’s model and HRI score provided better performance in recurrence prediction compared with traditional staging systems. The HRI score might serve as a promising RFS predictor for ICC with prognostic values.

Available only for authorised users

Shaib Y, El-Serag HB (2004) The epidemiology of cholangiocarcinoma. Semin Liver Dis 24(2):115–125. https://doi.org/10.1055/s-2004-828889 CrossRefPubMed

Massarweh NN, El-Serag HB (2017) Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Cancer Control 24(3):1073274817729245. https://doi.org/10.1177/1073274817729245 CrossRefPubMedPubMedCentral

Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D’Angelica M, DeMatteo RP, Fong Y, Schwartz L, Kemeny N, O’Reilly E, Abou-Alfa GK, Shimada H, Blumgart LH, Jarnagin WR (2008) Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg 248(1):84–96. https://doi.org/10.1097/SLA.0b013e318176c4d3 CrossRefPubMed

Nepal C, O’Rourke CJ, Oliveira DV, Taranta A, Shema S, Gautam P, Calderaro J, Barbour A, Raggi C, Wennerberg K, Wang XW, Lautem A, Roberts LR, Andersen JB (2017) Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Hepatology. https://doi.org/10.1002/hep.29764 CrossRef

Wang Y, Li J, Xia Y, Gong R, Wang K, Yan Z, Wan X, Liu G, Wu D, Shi L, Lau W, Wu M, Shen F (2013) Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy. J Clin Oncol 31(9):1188–1195. https://doi.org/10.1200/jco.2012.41.5984 CrossRefPubMed

Jiang Y, Zhang Q, Hu Y, Li T, Yu J, Zhao L, Ye G, Deng H, Mou T, Cai S, Zhou Z, Liu H, Chen G, Li G, Qi X (2018) ImmunoScore Signature: a prognostic and predictive tool in gastric cancer. Ann Surg 267(3):504–513. https://doi.org/10.1097/SLA.0000000000002116 CrossRefPubMed

Adam R, Bhangui P, Vibert E, Azoulay D, Pelletier G, Duclos-Vallee JC, Samuel D, Guettier C, Castaing D (2012) Resection or transplantation for early hepatocellular carcinoma in a cirrhotic liver: does size define the best oncological strategy? Ann Surg 256(6):883–891. https://doi.org/10.1097/SLA.0b013e318273bad0 CrossRefPubMed

Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, Wu WZ, Wang L, Tang ZY, Sun HC (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol 26(16):2707–2716. https://doi.org/10.1200/jco.2007.15.6521 CrossRefPubMed

Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25(18):2586–2593. https://doi.org/10.1200/jco.2006.09.4565 CrossRefPubMed

10.

Shi JY, Gao Q, Wang ZC, Zhou J, Wang XY, Min ZH, Shi YH, Shi GM, Ding ZB, Ke AW, Dai Z, Qiu SJ, Song K, Fan J (2013) Margin-infiltrating CD20(+) B cells display an atypical memory phenotype and correlate with favorable prognosis in hepatocellular carcinoma. Clin Cancer Res 19(21):5994–6005. https://doi.org/10.1158/1078-0432.CCR-12-3497 CrossRefPubMed

11.

Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, Fan J, Cao Y, Dai Z, Zhou J (2016) Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 150(7):1646–1658.e1617. https://doi.org/10.1053/j.gastro.2016.02.040 CrossRefPubMed

12.

Yi Y, He HW, Wang JX, Cai XY, Li YW, Zhou J, Cheng YF, Jin JJ, Fan J, Qiu SJ (2013) The functional impairment of HCC-infiltrating gammadelta T cells, partially mediated by regulatory T cells in a TGFbeta- and IL-10-dependent manner. J Hepatol 58(5):977–983. https://doi.org/10.1016/j.jhep.2012.12.015 CrossRefPubMed

13.

Gu FM, Gao Q, Shi GM, Zhang X, Wang J, Jiang JH, Wang XY, Shi YH, Ding ZB, Fan J, Zhou J (2012) Intratumoral IL-17(+) cells and neutrophils show strong prognostic significance in intrahepatic cholangiocarcinoma. Ann Surg Oncol 19(8):2506–2514. https://doi.org/10.1245/s10434-012-2268-8 CrossRefPubMed

14.

Sabbatino F, Villani V, Yearley JH, Deshpande V, Cai L, Konstantinidis IT, Moon C, Nota S, Wang Y, Al-Sukaini A, Zhu AX, Goyal L, Ting DT, Bardeesy N, Hong TS, Fernandez-del Castillo C, Tanabe KK, Lillemoe KD, Ferrone S, Ferrone CR (2016) PD-L1 and HLA class I antigen expression and clinical course of the disease in intrahepatic cholangiocarcinoma. Clin Cancer Res 22(2):470–478. https://doi.org/10.1158/1078-0432.CCR-15-0715 CrossRefPubMed

15.

Ghesquiere B, Wong BW, Kuchnio A, Carmeliet P (2014) Metabolism of stromal and immune cells in health and disease. Nature 511(7508):167–176. https://doi.org/10.1038/nature13312 CrossRefPubMed

16.

IARC, Bosman FT, Carneiro F, Hruban RH, Theise ND (2010) WHO classification of tumours of the digestive system, Fourth Edition. World Health Organization

17.

Li H, Li X, Liu S, Guo L, Zhang B, Zhang J, Ye Q (2017) Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1. Hepatology 66(6):1920–1933. https://doi.org/10.1002/hep.29360 CrossRefPubMed

18.

Li YW, Qiu SJ, Fan J, Zhou J, Gao Q, Xiao YS, Xu YF (2011) Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 54(3):497–505. https://doi.org/10.1016/j.jhep.2010.07.044 CrossRefPubMed

19.

Fu J, Zhang Z, Zhou L, Qi Z, Xing S, Lv J, Shi J, Fu B, Liu Z, Zhang JY, Jin L, Zhao Y, Lau GK, Zhao J, Wang FS (2013) Impairment of CD4 + cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma. Hepatology 58(1):139–149. https://doi.org/10.1002/hep.26054 CrossRefPubMed

20.

Gabrielson A, Wu Y, Wang H, Jiang J, Kallakury B, Gatalica Z, Reddy S, Kleiner D, Fishbein T, Johnson L, Island E, Satoskar R, Banovac F, Jha R, Kachhela J, Feng P, Zhang T, Tesfaye A, Prins P, Loffredo C, Marshall J, Weiner L, Atkins M, He AR (2016) Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res 4(5):419–430. https://doi.org/10.1158/2326-6066.CIR-15-0110 CrossRefPubMedPubMedCentral

21.

Gao Q, Zhou J, Wang XY, Qiu SJ, Song K, Huang XW, Sun J, Shi YH, Li BZ, Xiao YS, Fan J (2012) Infiltrating memory/senescent T cell ratio predicts extrahepatic metastasis of hepatocellular carcinoma. Ann Surg Oncol 19(2):455–466. https://doi.org/10.1245/s10434-011-1864-3 CrossRefPubMed

22.

Asai A, Tsuchimoto Y, Ohama H, Fukunishi S, Tsuda Y, Kobayashi M, Higuchi K, Suzuki F (2017) Host antitumor resistance improved by the macrophage polarization in a chimera model of patients with HCC. Oncoimmunology 6(4):e1299301. https://doi.org/10.1080/2162402X.2017.1299301 CrossRefPubMedPubMedCentral

23.

Garnelo M, Tan A, Her Z, Yeong J, Lim CJ, Chen J, Lim KH, Weber A, Chow P, Chung A, Ooi LL, Toh HC, Heikenwalder M, Ng IO, Nardin A, Chen Q, Abastado JP, Chew V (2017) Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 66(2):342–351. https://doi.org/10.1136/gutjnl-2015-310814 CrossRefPubMed

24.

Takata Y, Nakamoto Y, Nakada A, Terashima T, Arihara F, Kitahara M, Kakinoki K, Arai K, Yamashita T, Sakai Y, Yamashita T, Mizukoshi E, Kaneko S (2011) Frequency of CD45RO + subset in CD4 + CD25(high) regulatory T cells associated with progression of hepatocellular carcinoma. Cancer Lett 307(2):165–173. https://doi.org/10.1016/j.canlet.2011.03.029 CrossRefPubMed

25.

Wang L, Sun Y, Zhang Z, Jia Y, Zou Z, Ding J, Li Y, Xu X, Jin L, Yang T, Li Z, Sun Y, Zhang JY, Lv S, Chen L, Li B, Gershwin ME, Wang FS (2015) CXCR25 + CD4 + T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis. Hepatology 61(2):627–638. https://doi.org/10.1002/hep.27306 CrossRefPubMed

26.

Zhang HH, Mei MH, Fei R, Liao WJ, Wang XY, Qin LL, Wang JH, Wei L, Chen HS (2010) Regulatory T cell depletion enhances tumor specific CD8 T-cell responses, elicited by tumor antigen NY-ESO-1b in hepatocellular carcinoma patients, in vitro. Int J Oncol 36(4):841–848PubMed

27.

Liu WR, Tian MX, Jin L, Yang LX, Ding ZB, Shen YH, Peng YF, Zhou J, Qiu SJ, Dai Z, Fan J, Shi YH (2014) High expression of 5-hydroxymethylcytosine and isocitrate dehydrogenase 2 is associated with favorable prognosis after curative resection of hepatocellular carcinoma. J Exp Clin Cancer Res CR 33:32. https://doi.org/10.1186/1756-9966-33-32 CrossRefPubMed

28.

Li S, Xu F, Li H, Zhang J, Zhong A, Huang B, Lai M (2017) S100A8(+) stroma cells predict a good prognosis and inhibit aggressiveness in colorectal carcinoma. Oncoimmunology 6(1):e1260213. https://doi.org/10.1080/2162402X.2016.1260213 CrossRefPubMed

29.

Zhang JX, Song W, Chen ZH, Wei JH, Liao YJ, Lei J, Hu M, Chen GZ, Liao B, Lu J, Zhao HW, Chen W, He YL, Wang HY, Xie D, Luo JH (2013) Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis. Lancet Oncol 14(13):1295–1306. https://doi.org/10.1016/S1470-2045(13)70491-1 CrossRefPubMed

30.

Frank E, Harrell J Hmisc: Harrell Miscellaneous. R Package version 3.9-2. http://CRAN.Rproject.org/package=Hmisc

31.

Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10(21):7252–7259. https://doi.org/10.1158/1078-0432.ccr-04-0713 CrossRefPubMed

32.

Mina M, Boldrini R, Citti A, Romania P, D’Alicandro V, De Ioris M, Castellano A, Furlanello C, Locatelli F, Fruci D (2015) Tumor-infiltrating T lymphocytes improve clinical outcome of therapy-resistant neuroblastoma. Oncoimmunology 4(9):e1019981. https://doi.org/10.1080/2162402X.2015.1019981 CrossRefPubMedPubMedCentral

33.

Geissler K, Fornara P, Lautenschlager C, Holzhausen HJ, Seliger B, Riemann D (2015) Immune signature of tumor infiltrating immune cells in renal cancer. Oncoimmunology 4(1):e985082. https://doi.org/10.4161/2162402X.2014.985082 CrossRefPubMedPubMedCentral

34.

Chang W, Gao X, Han Y, Du Y, Liu Q, Wang L, Tan X, Zhang Q, Liu Y, Zhu Y, Yu Y, Fan X, Zhang H, Zhou W, Wang J, Fu C, Cao G (2014) Gene expression profiling-derived immunohistochemistry signature with high prognostic value in colorectal carcinoma. Gut 63(9):1457–1467. https://doi.org/10.1136/gutjnl-2013-305475 CrossRefPubMed

35.

Nault JC, De Reynies A, Villanueva A, Calderaro J, Rebouissou S, Couchy G, Decaens T, Franco D, Imbeaud S, Rousseau F, Azoulay D, Saric J, Blanc JF, Balabaud C, Bioulac-Sage P, Laurent A, Laurent-Puig P, Llovet JM, Zucman-Rossi J (2013) A hepatocellular carcinoma 5-gene score associated with survival of patients after liver resection. Gastroenterology 145(1):176–187. https://doi.org/10.1053/j.gastro.2013.03.051 CrossRefPubMed

36.

Jiang Y, Zhang Q, Hu Y, Li T, Yu J, Zhao L, Ye G, Deng H, Mou T, Cai S, Zhou Z, Liu H, Chen G, Li G, Qi X (2016) ImmunoScore Signature: a prognostic and predictive tool in gastric cancer. Ann Surg 10:15. https://doi.org/10.1097/sla.0000000000002116 CrossRef

37.

Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013 CrossRefPubMed

38.

Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306. https://doi.org/10.1038/nrc3245 CrossRefPubMed

39.

Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, Lagorce C, Wind P, Marliot F, Bruneval P, Zatloukal K, Trajanoski Z, Berger A, Fridman WH, Galon J (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27(35):5944–5951. https://doi.org/10.1200/JCO.2008.19.6147 CrossRefPubMed

40.

Wen T, Wang Z, Li Y, Li Z, Che X, Fan Y, Wang S, Qu J, Yang X, Hou K, Zhou W, Xu L, Li C, Wang J, Liu J, Chen L, Zhang J, Qu X, Liu Y (2017) A four-factor immunoscore system that predicts clinical outcome for stage II/III gastric cancer. Cancer Immunol Res 5(7):524–534. https://doi.org/10.1158/2326-6066.cir-16-0381 CrossRefPubMed

41.

Angell H, Galon J (2013) From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol 25(2):261–267. https://doi.org/10.1016/j.coi.2013.03.004 CrossRefPubMed

42.

Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF (2013) Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci Transl Med 5(200):200ra116. https://doi.org/10.1126/scitranslmed.3006504 CrossRefPubMedPubMedCentral

43.

Mougiakakos D, Johansson CC, Kiessling R (2009) Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood 113(15):3542–3545. https://doi.org/10.1182/blood-2008-09-181040 CrossRefPubMed

44.

Gordon-Weeks AN, Lim SY, Yuzhalin AE, Jones K, Markelc B, Kim KJ, Buzzelli JN, Fokas E, Cao Y, Smart S, Muschel R (2017) Neutrophils promote hepatic metastasis growth through fibroblast growth factor 2-dependent angiogenesis in mice. Hepatology 65(6):1920–1935. https://doi.org/10.1002/hep.29088 CrossRefPubMed

45.

Rava M, D’Andrea A, Doni M, Kress TR, Ostuni R, Bianchi V, Morelli MJ, Collino A, Ghisletti S, Nicoli P, Recordati C, Iascone M, Sonzogni A, D’Antiga L, Shukla R, Faulkner GJ, Natoli G, Campaner S, Amati B (2017) Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18. Hepatology 65(5):1708–1719. https://doi.org/10.1002/hep.28942 CrossRefPubMed

46.

Lin C, He H, Liu H, Li R, Chen Y, Qi Y, Jiang Q, Chen L, Zhang P, Zhang H, Li H, Zhang W, Sun Y, Xu J (2019) Tumour-associated macrophages-derived CXCL8 determines immune evasion through autonomous PD-L1 expression in gastric cancer. Gut 10:15. https://doi.org/10.1136/gutjnl-2018-316324 CrossRef

47.

Shi RY, Yang XR, Shen QJ, Yang LX, Xu Y, Qiu SJ, Sun YF, Zhang X, Wang Z, Zhu K, Qin WX, Tang ZY, Fan J, Zhou J (2013) High expression of Dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma patients after surgery. Cancer 119(5):993–1003. https://doi.org/10.1002/cncr.27788 CrossRefPubMed

48.

Jiang W, Zeng ZC, Tang ZY, Fan J, Sun HC, Zhou J, Zeng MS, Zhang BH, Ji Y, Chen YX (2011) A prognostic scoring system based on clinical features of intrahepatic cholangiocarcinoma: the Fudan score. Ann Oncol 22(7):1644–1652. https://doi.org/10.1093/annonc/mdq650 CrossRefPubMed

49.

Johnson PJ, Berhane S, Kagebayashi C, Satomura S, Teng M, Reeves HL, O’Beirne J, Fox R, Skowronska A, Palmer D, Yeo W, Mo F, Lai P, Inarrairaegui M, Chan SL, Sangro B, Miksad R, Tada T, Kumada T, Toyoda H (2015) Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol 33(6):550–558. https://doi.org/10.1200/jco.2014.57.9151 CrossRefPubMed

50.

Mok Y, Son DK, Yun YD, Jee SH, Samet JM (2016) gamma-Glutamyltransferase and cancer risk: the Korean cancer prevention study. Int J Cancer 138(2):311–319. https://doi.org/10.1002/ijc.29659 CrossRefPubMed

Title: Histopathology-based immunoscore predicts recurrence for intrahepatic cholangiocarcinoma after hepatectomy
Authors: Meng-Xin Tian
Yu-Fu Zhou
Wei-Feng Qu
Wei-Ren Liu
Lei Jin
Xi-Fei Jiang
Han Wang
Chen-Yang Tao
Pei-Yun Zhou
Yuan Fang
Zhen-Bin Ding
Yuan-Fei Peng
Jian Zhou
Jia Fan
Ying-Hong Shi
Publication date: 01-08-2019
Publisher: Springer Berlin Heidelberg
Keywords: Cholangiocarcinoma
Cholangiocarcinoma
Published in: Cancer Immunology, Immunotherapy / Issue 8/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-019-02371-3

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2019

High levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the serum are associated with poor prognosis in HPV-negative squamous cell oropharyngeal cancer

Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1)

Interferon beta increases NK cell cytotoxicity against tumor cells in patients with nasopharyngeal carcinoma via tumor necrosis factor apoptosis-inducing ligand

Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study

An IL-15-based superagonist ALT-803 enhances the NK cell response to cetuximab-treated squamous cell carcinoma of the head and neck

Reduced CTL motility and activity in avascular tumor areas

Keynote webinar | Spotlight on antibody–drug conjugates in cancer