Skip to main content
Top
Published in: Annals of Surgical Oncology 8/2012

01-08-2012 | Hepatobiliary Tumors

Intratumoral IL-17+ Cells and Neutrophils show Strong Prognostic Significance in Intrahepatic Cholangiocarcinoma

Authors: Fang-Ming Gu, MD, Qiang Gao, MD, Guo-Ming Shi, MD, Xin Zhang, MD, Jiping Wang, MD, Jia-Hao Jiang, MD, Xiao-Ying Wang, MD, Ying-Hong Shi, MD, Zhen-Bin Ding, MD, Jia Fan, MD, Jian Zhou, MD

Published in: Annals of Surgical Oncology | Issue 8/2012

Login to get access

Abstract

Background

Inflammatory reactions at a tumor site have both detrimental and beneficial effects on tumor progression. This study was designed to assess the clinical significance of tumor-infiltrating inflammatory cells in patients with intrahepatic cholangiocarcinoma (ICC).

Methods

A total of 123 consecutive ICC patients who underwent curative resection were enrolled. Tissue microarray and immunohistochemistry were used to analyze the distribution and clinical relevance of IL-17+, FOXP3+, CD8+, CD66b+ cells, and microvessel density (CD34) in different microanatomical areas.

Results

IL-17+ cells, FOXP3+ lymphocytes, CD66b+ neutrophils, and microvessels were enriched predominantly in intratumor (IT) area, whereas CD8+ lymphocytes were most abundant in tumor invasive front. On univariate analyses, increasing IL-17 IT + and neutrophilsIT were significantly associated with worse patient survival. Multivariate analyses revealed that IL-17 IT + (hazard ratio [HR] = 1.59; 95% confidence interval [CI], 1.05–2.41; P = 0.028), neutrophilsIT (HR = 1.76; 95% CI, 1.16–2.65; P = 0.007), and their combination (HR 2.8; 95% CI 1.72–4.57; P < 0.001) were independent prognostic factors, which were superior to conventional clinicopathologic features, such as intrahepatic metastasis and TNM stage. IL-17 IT + significantly correlated with the presence of lymph node metastasis, intrahepatic metastasis, and advanced stages, whereas neutrophilsIT correlated with the presence of vascular invasion. In addition, significant positive correlations were detected among densities of IL-17+ cells, neutrophils, and microvessel density.

Conclusions

Our data suggested that intratumor IL-17+ cells, neutrophils are novel, powerful predictors of prognosis in patients with ICC.
Appendix
Available only for authorised users
Literature
1.
go back to reference Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology. 2008;48:308–21.PubMedCrossRef Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology. 2008;48:308–21.PubMedCrossRef
2.
go back to reference 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, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248:84–96.PubMedCrossRef 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, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248:84–96.PubMedCrossRef
3.
4.
go back to reference Gomez D, Morris-Stiff G, Toogood G, Lodge J, Prasad K. Impact of systemic inflammation on outcome following resection for intrahepatic cholangiocarcinoma. J Surg Oncol. 2008;97:513–8.PubMedCrossRef Gomez D, Morris-Stiff G, Toogood G, Lodge J, Prasad K. Impact of systemic inflammation on outcome following resection for intrahepatic cholangiocarcinoma. J Surg Oncol. 2008;97:513–8.PubMedCrossRef
5.
go back to reference Sirica A. Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy. Hepatology. 2005;41:5–15.PubMedCrossRef Sirica A. Cholangiocarcinoma: molecular targeting strategies for chemoprevention and therapy. Hepatology. 2005;41:5–15.PubMedCrossRef
6.
7.
8.
go back to reference Takagi S, Miyagawa S, Ichikawa E, Soeda J, Miwa S, Miyagawa Y, Iijima S, Noike T, Kobayashi A, Kawasaki S. Dendritic cells, T-cell infiltration, and Grp94 expression in cholangiocellular carcinoma. Human Pathol. 2004;35:881–6.CrossRef Takagi S, Miyagawa S, Ichikawa E, Soeda J, Miwa S, Miyagawa Y, Iijima S, Noike T, Kobayashi A, Kawasaki S. Dendritic cells, T-cell infiltration, and Grp94 expression in cholangiocellular carcinoma. Human Pathol. 2004;35:881–6.CrossRef
9.
go back to reference Shimonishi T, Isse K, Shibata F, Aburatani I, Tsuneyama K, Sabit H, Harada K, Miyazaki K, Nakanuma Y. Up-regulation of Fas ligand at early stages and down-regulation of Fas at progressed stages of intrahepatic cholangiocarcinoma reflect evasion from immune surveillance. Hepatology. 2000;32:761–9.PubMedCrossRef Shimonishi T, Isse K, Shibata F, Aburatani I, Tsuneyama K, Sabit H, Harada K, Miyazaki K, Nakanuma Y. Up-regulation of Fas ligand at early stages and down-regulation of Fas at progressed stages of intrahepatic cholangiocarcinoma reflect evasion from immune surveillance. Hepatology. 2000;32:761–9.PubMedCrossRef
10.
go back to reference 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;100:500–4.PubMedCrossRef 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;100:500–4.PubMedCrossRef
11.
go back to reference Hasita H, Komohara Y, Okabe H, Masuda T, Ohnishi K, Lei XF, Beppu T, Baba H, Takeya M. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 2010;101:1913–9.PubMedCrossRef Hasita H, Komohara Y, Okabe H, Masuda T, Ohnishi K, Lei XF, Beppu T, Baba H, Takeya M. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 2010;101:1913–9.PubMedCrossRef
12.
go back to reference Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007;25:2586–93.PubMedCrossRef Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007;25:2586–93.PubMedCrossRef
13.
go back to reference Yakirevich E, Resnick MB. Regulatory T lymphocytes: pivotal components of the host antitumor response. J Clin Oncol 2007;25:2506–8.PubMedCrossRef Yakirevich E, Resnick MB. Regulatory T lymphocytes: pivotal components of the host antitumor response. J Clin Oncol 2007;25:2506–8.PubMedCrossRef
14.
go back to reference Zou W, Restifo NP. TH17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 2010;10:248–56.PubMedCrossRef Zou W, Restifo NP. TH17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 2010;10:248–56.PubMedCrossRef
15.
go back to reference Wilke CM, Kryczek I, Wei S, Zhao E, Wu K, Wang G, Zou W. Th17 cells in cancer: help or hindrance? Carcinogenesis 2011 32:643–9.PubMedCrossRef Wilke CM, Kryczek I, Wei S, Zhao E, Wu K, Wang G, Zou W. Th17 cells in cancer: help or hindrance? Carcinogenesis 2011 32:643–9.PubMedCrossRef
16.
go back to reference Nathan H, Pawlik TM. Staging of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 2010;26:269–73.PubMedCrossRef Nathan H, Pawlik TM. Staging of intrahepatic cholangiocarcinoma. Curr Opin Gastroenterol 2010;26:269–73.PubMedCrossRef
17.
go back to reference Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009;15:971–9.PubMedCrossRef Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J. Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 2009;15:971–9.PubMedCrossRef
18.
go back to reference Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 2010;51:154–64.PubMedCrossRef Kuang DM, Peng C, Zhao Q, Wu Y, Chen MS, Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 2010;51:154–64.PubMedCrossRef
20.
go back to reference Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 2009;114:1141–9.PubMedCrossRef Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S, Huang E, Finlayson E, Simeone D, Welling TH. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 2009;114:1141–9.PubMedCrossRef
21.
go back to reference fanos K, Bruno T, Maris C, Xu L, Thoburn C, DeMarzo A, Meeker A, Isaacs W, Drake C. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 2008; 14:3254–61.PubMedCrossRef fanos K, Bruno T, Maris C, Xu L, Thoburn C, DeMarzo A, Meeker A, Isaacs W, Drake C. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res 2008; 14:3254–61.PubMedCrossRef
22.
go back to reference Lv L, Pan K, Li XD, She KL, Zhao JJ, Wang W, Chen JG, Chen YB, Yun JP, Xia JC. The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma. PLoS One 2011;6:e18219.PubMedCrossRef Lv L, Pan K, Li XD, She KL, Zhao JJ, Wang W, Chen JG, Chen YB, Yun JP, Xia JC. The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma. PLoS One 2011;6:e18219.PubMedCrossRef
23.
go back to reference Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F, Galon J. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011;71:1263–71.PubMedCrossRef Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, Berger A, Bruneval P, Fridman WH, Pages F, Galon J. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res 2011;71:1263–71.PubMedCrossRef
24.
25.
go back to reference Kuang D, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, Yin X, Zheng L. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol 2011;54:948–55.PubMedCrossRef Kuang D, Zhao Q, Wu Y, Peng C, Wang J, Xu Z, Yin X, Zheng L. Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol 2011;54:948–55.PubMedCrossRef
26.
go back to reference Jensen H, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, von der Maase H. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 2009;27:4709–17.PubMedCrossRef Jensen H, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, von der Maase H. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 2009;27:4709–17.PubMedCrossRef
27.
go back to reference Li Y, Qiu S, Fan J, Zhou J, Gao Q, Xiao Y, Xu Y. Intratumoral neutrophils as poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 2011;54:497–505.PubMedCrossRef Li Y, Qiu S, Fan J, Zhou J, Gao Q, Xiao Y, Xu Y. Intratumoral neutrophils as poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 2011;54:497–505.PubMedCrossRef
28.
29.
30.
go back to reference Shojaei F, Singh M, Thompson J, Ferrara N. Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci USA 2008;105:2640-5.PubMedCrossRef Shojaei F, Singh M, Thompson J, Ferrara N. Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression. Proc Natl Acad Sci USA 2008;105:2640-5.PubMedCrossRef
31.
go back to reference Murdoch C, Muthana M, Coffelt S, Lewis C. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008;8:618-31.PubMedCrossRef Murdoch C, Muthana M, Coffelt S, Lewis C. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 2008;8:618-31.PubMedCrossRef
32.
go back to reference Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436–44.PubMedCrossRef Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436–44.PubMedCrossRef
33.
go back to reference Pittet MJ. Behavior of immune players in the tumor microenvironment. Curr Opin Oncol 2009;21:53–9.PubMedCrossRef Pittet MJ. Behavior of immune players in the tumor microenvironment. Curr Opin Oncol 2009;21:53–9.PubMedCrossRef
Metadata
Title
Intratumoral IL-17+ Cells and Neutrophils show Strong Prognostic Significance in Intrahepatic Cholangiocarcinoma
Authors
Fang-Ming Gu, MD
Qiang Gao, MD
Guo-Ming Shi, MD
Xin Zhang, MD
Jiping Wang, MD
Jia-Hao Jiang, MD
Xiao-Ying Wang, MD
Ying-Hong Shi, MD
Zhen-Bin Ding, MD
Jia Fan, MD
Jian Zhou, MD
Publication date
01-08-2012
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 8/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-012-2268-8

Other articles of this Issue 8/2012

Annals of Surgical Oncology 8/2012 Go to the issue