Targeted Oncology

, Volume 12, Issue 2, pp 211–218 | Cite as

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

  • Yu Jin Lim
  • Jaemoon Koh
  • Kyubo KimEmail author
  • Eui Kyu Chie
  • Sehui Kim
  • Kyoung Bun Lee
  • Jin-Young Jang
  • Sun Whe Kim
  • Do-Youn Oh
  • Yung-Jue Bang
Original Research Article



There currently is only limited knowledge on the role of tumor-specific immunity in cholangiocarcinoma.


This study evaluated the clinical implications of cytotoxic T lymphocyte antigen-4 (CTLA-4) expression levels and CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) in extrahepatic bile duct (EHBD) cancer.

Patients and Methods

Immunohistochemistry of CTLA-4, CD4, and CD8 was performed for 77 EHBD cancer patients undergoing surgery plus adjuvant chemoradiotherapy. CTLA-4 expression on tumor cells and TILs were assessed by using H-scores and the proportion of CTLA-4+ lymphocytes, respectively.


With optimal cutoff values determined by a maximal chi-square method with overall survival (OS) data, patients with CTLA-4 H-score >70 and a proportion of CTLA-4+ TILs >0.15 showed higher mean density of CD8+ and CD4+ TILs, respectively (P = 0.025 for CD8+ and P = 0.055 for CD4+ TILs). The high CTLA-4 H-score level was associated with prolonged OS and disease-free interval (DFI) (P = 0.025 and 0.004, respectively). With differential levels of CTLA-4 H-score according to hilar and non-hilar locations (high rate 32 vs. 68%, respectively; P = 0.013), an exploratory subgroup analysis demonstrated that the associations between the CTLA-4 expression and OS and DFI were confined to hilar tumors (P = 0.003 and <0.001, respectively), but not to non-hilar ones (P = 0.613 and 0.888, respectively).


This study demonstrates a potential prognostic relevance of CTLA-4 expression in EHBD cancer. We suggest a differential survival impact of the CTLA-4 expression level according to different tumor locations.


Overall Survival Cholangiocarcinoma Ipilimumab Extrahepatic Bile Duct Biliary Tract Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Compliance with Ethical Standards



Conflict of Interest

The authors declare no conflicts of interest.

Supplementary material

11523_2016_474_MOESM1_ESM.docx (298 kb)
Supplementary Fig. 1 (DOCX 298 kb)
11523_2016_474_MOESM2_ESM.docx (18 kb)
Supplementary Table 1 (DOCX 18 kb)
11523_2016_474_MOESM3_ESM.docx (20 kb)
Supplementary Table 2 (DOCX 19 kb)


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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Yu Jin Lim
    • 1
  • Jaemoon Koh
    • 2
  • Kyubo Kim
    • 3
    Email author
  • Eui Kyu Chie
    • 1
  • Sehui Kim
    • 2
  • Kyoung Bun Lee
    • 2
  • Jin-Young Jang
    • 4
  • Sun Whe Kim
    • 4
  • Do-Youn Oh
    • 5
  • Yung-Jue Bang
    • 5
  1. 1.Department of Radiation OncologySeoul National University College of MedicineSeoulRepublic of Korea
  2. 2.Department of PathologySeoul National University College of MedicineSeoulRepublic of Korea
  3. 3.Department of Radiation OncologyEwha Womans University School of MedicineSeoulRepublic of Korea
  4. 4.Department of SurgerySeoul National University College of MedicineSeoulRepublic of Korea
  5. 5.Department of Internal MedicineSeoul National University College of MedicineSeoulRepublic of Korea

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