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Program Death 1 Immune Checkpoint and Tumor Microenvironment: Implications for Patients With Intrahepatic Cholangiocarcinoma

  • Hepatobiliary Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Program death 1 (PD-1) and its ligand (PD-L1) have been identified as potential therapeutic targets for solid and hematologic malignancies. The current study aimed to assess PD-L1 expression in intrahepatic cholangiocarcinoma (ICC) and relate clinical outcomes to its expression.

Methods

Formalin-fixed, paraffin-embedded tumor specimens were obtained for patients undergoing surgery at Johns Hopkins Hospital between 1991 and 2011. Immunohistochemistry was used to assess PD-L1 expression in tumor-associated macrophages (TAMs) and within the tumor front (TF).

Results

Of 54 tumor samples analyzed, 34 stained positive for PD-L1 expression on TAMs (TAMs+), and 39 stained positive for PD-L1 expression on cells within the tumor front (TF+). The TF+ patients were less likely to present with metastatic lymph nodes (N1 patients: 26.7 vs 7.7 %; p = 0.011), whereas all tumors with intrahepatic metastasis failed to demonstrate staining for PD-L1 around the tumor front (p = 0.020). Patients with tumors shown to be TAMs+ were less likely to present with multiple lesions (35.0 vs 8.8 %; p = 0.017). Patients with tumors exhibiting PD-L1 expression around the tumor front demonstrated a worse overall survival than TF patients (p = 0.008). Multivariable analysis showed that patients with tumors staining for PD-L1 in the tumor front had a 59.5 % reduced survival (TF− vs TF+: time ratio, 0.405; 95 % confidence interval, 0.215–0.761; p = 0.005).

Conclusion

Expression of PD-L1 was noted among a majority of patients, and PD-L1 expression within the tumor front was associated with a 60 % decreased survival. Future clinical trials are necessary to assess the safety and efficacy of anti-PD-L1 therapies among patients with ICC.

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References

  1. Bridgewater J, Galle PR, Khan SA, et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J Hepatol. 2014;60:1268–89.

    Article  PubMed  Google Scholar 

  2. Aljiffry M, Abdulelah A, Walsh M, et al. Evidence-based approach to cholangiocarcinoma: a systematic review of the current literature. J Am Coll Surg. 2009;208:134–47.

    Article  PubMed  Google Scholar 

  3. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24:115–25.

    Article  PubMed  Google Scholar 

  4. YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase? J Hepatol. 2004;40:472–7.

    Article  PubMed  Google Scholar 

  5. 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;366:2443–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schultheis AM, Scheel AH, Ozretić L, et al. PD-L1 expression in small cell neuroendocrine carcinomas. Eur J Cancer. 2015;51:421–6.

    Article  CAS  PubMed  Google Scholar 

  9. Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5:43–51.

    Article  CAS  PubMed  Google Scholar 

  10. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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;100:500–4.

    Article  PubMed  Google Scholar 

  12. Soares KC, Rucki AA, Wu AA, et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J Immunother. 2015;38:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–17.

    Article  CAS  PubMed  Google Scholar 

  14. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012; 4:127ra37.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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(2), 470–478.

    Article  CAS  PubMed  Google Scholar 

  17. Leyva-Illades D, McMillin M, Quinn M, et al. Cholangiocarcinoma pathogenesis: role of the tumor microenvironment. Transl Gastrointest Cancer. 2012;1:71–80. Retrieved 7 Sep 2015 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3448449&tool=pmcentrez&rendertype=abstract.

  18. Hasita H, Komohara Y, Okabe H, et al. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 2010;101:1913–9.

    Article  CAS  PubMed  Google Scholar 

  19. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011;54:173–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ramanathan S, Jagannathan N. Tumor-associated macrophage: a review on the phenotypes, traits, and functions. Iran J Cancer Prev. 2014;7:1–8. Retrieved 2 Sep 2015 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4142950&tool=pmcentrez&rendertype=abstract.

  21. Liengswangwong U, Nitta T, Kashiwagi H, et al. Infrequent microsatellite instability in liver fluke infection-associated intrahepatic cholangiocarcinomas from Thailand. Int J Cancer. 2003;107:375–80.

    Article  CAS  PubMed  Google Scholar 

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Conflict of interest

Dr. Robert A. Anders receives research funding from Bristol-Myers Squibb and Five Prime Diagnostics. The remaining authors have no conflicts of interests.

Author information

Author notes

  1. Feriyl Bhaijjee MD

    Present address: Department of Pathology, AmeriPath Indiana, Indianapolis, IN, USA

Authors and Affiliations

  1. Department of Surgery, John Hopkins University School of Medicine, Baltimore, MD, USA

    Faiz Gani MBBS, Neeraja Nagarajan MD, MPH, Yuhree Kim MD, MPH & Timothy M. Pawlik MD, MPH, PhD, FACS, FRACS (Hon.)

  2. Division of Gastrointestinal and Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Qingfeng Zhu MD, Lan Luan MD, Feriyl Bhaijjee MD & Robert A. Anders MD, PhD

  3. Division of Surgical Oncology, Department of Surgery, John L. Cameron Professor of Alimentary Tract Surgery, Johns Hopkins Hospital, Baltimore, MD, USA

    Timothy M. Pawlik MD, MPH, PhD, FACS, FRACS (Hon.)

Authors
  1. Faiz Gani MBBS
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  2. Neeraja Nagarajan MD, MPH
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  3. Yuhree Kim MD, MPH
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  4. Qingfeng Zhu MD
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  5. Lan Luan MD
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  6. Feriyl Bhaijjee MD
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  7. Robert A. Anders MD, PhD
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  8. Timothy M. Pawlik MD, MPH, PhD, FACS, FRACS (Hon.)
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Corresponding authors

Correspondence to Robert A. Anders MD, PhD or Timothy M. Pawlik MD, MPH, PhD, FACS, FRACS (Hon.).

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Gani, F., Nagarajan, N., Kim, Y. et al. Program Death 1 Immune Checkpoint and Tumor Microenvironment: Implications for Patients With Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 23, 2610–2617 (2016). https://doi.org/10.1245/s10434-016-5101-y

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  • DOI: https://doi.org/10.1245/s10434-016-5101-y

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