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Cancer Immunology, Immunotherapy

, Volume 67, Issue 3, pp 435–444 | Cite as

The Immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases

  • Yun Wang
  • Hao-cheng Lin
  • Ma-yan Huang
  • Qiong Shao
  • Zhi-qiang Wang
  • Feng-hua Wang
  • Yun-fei Yuan
  • Bin-kui Li
  • De-shen Wang
  • Pei-rong Ding
  • Gong Chen
  • Xiao-jun Wu
  • Zhen-hai Lu
  • Li-ren Li
  • Zhi-zhong Pan
  • Peng Sun
  • Shu-mei Yan
  • De-sen Wan
  • Rui-hua XuEmail author
  • Yu-hong LiEmail author
Original Article

Abstract

Background

The Immunoscore was initially established to evaluate the prognosis of stage I/II/III colorectal cancer patients. However, the feasibility of the Immunoscore for the prognosis of colorectal cancer liver metastases (CRCLM) has not been reported.

Methods

Liver metastases in 249 CRCLM patients were retrospectively analyzed. The Immunoscore was assessed according to the counts and densities of CD3+ and CD8+ T cells in the central- and peritumoral areas by immunohistochemistry. The prognostic role of the Immunoscore for relapse–free survival (RFS) and overall survival (OS) was analyzed with Kaplan–Meier curves and Cox multivariate models, and confirmed via an internal validation. Receiver operating characteristic (ROC) curves were plotted to compare the prognostic values of the Immunoscore and the clinical risk score (CRS) system.

Results

CRCLM patients with high Immunoscores (> 2) had significantly longer RFS [median RFS (95% confidence interval; 95% CI) 21.4 (7.8–35.1) vs. 8.7 (6.8–10.5) months, P < 0.001] and OS [median OS (95% CI): not reached vs. 28.7 (23.2–34.2) months, P < 0.001] than those with low Immunoscores (≤ 2). After stratification by CRS, the Immunoscore retained a statistically significant prognostic value for OS. The areas under the ROC curves (AUROCs) of the Immunoscore and the CRS system for RFS were 0.711 [95% CI 0.642–0.781] and 0.675[95% CI 0.601–0.749] (P = 0.492), whereas the AUROC of the Immunoscore system for OS was larger than that of the CRS system [0.759 (95% CI 0.699–0.818) vs. 0.660 (95% CI 0.592–0.727); P = 0.029].

Conclusions

The Immunoscore of liver metastases can be applied to predict the prognosis of CRCLM patients following liver resection.

Keywords

Colorectal cancer liver metastases Tumor-infiltrating lymphocyte Immunoscore Prognosis 

Abbreviations

AUROC

Area under the ROC curve

CAPEOX

Oxaliplatin and capecitabine

CEA

Carcinoembryonic antigen

CI

Confidence interval

CRC

Colorectal cancer

CRCLM

Colorectal cancer liver metastases

CRS

Clinical risk score

CT

Center tumor

ESMO

European society for medical oncology

FOLFIRI

Irinotecan, 5-Fu and leucovorin

FOLFOX

Oxaliplatin, 5-Fu and leucovorin

FOLFOXIRI

Oxaliplatin, irinotecan, 5-Fu and leucovorin

GZMB

Granzyme B

HAI

Hepatic arterial infusion

HR

Hazard ratio

IM

Invasive margin

IQR

Interquartile range

LV

Leucovorin

OS

Overall survival

RFS

Relapse-free survival

ROC

Receiver operating characteristic

TIL

Tumor-infiltrating lymphocyte

Tregs

T-regulatory cells

XELIRI

Irinotecan and capecitabine

Notes

Acknowledgements

We express our gratitude to all the patients for their participation in this study. We also appreciate all our colleagues at the Sun Yat-sen University Cancer Center who participated in administering the treatment in the current study. Medbanks (Beijing) Network Technology Co., Ltd. is thanked for data collection.

Author contribution

YL and RX were involved in the study design, protocol development, and data analysis and interpretation. MH and QS performed the immunohistochemical staining. SY and PS contributed to the Immunoscore evaluation. YW and HL performed the literature search for the study and were involved in data interpretation and writing the report. ZW, FW, YY, BL, DW, PD, GC, XW, ZL, LL, ZP and DW contributed to data collection. All authors reviewed and approved the manuscript for submission.

Funding

The work was supported by the Science and Technology Planning Project of Guangdong Province, China (201508020247).

Compliance with ethical standards

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

262_2017_2094_MOESM1_ESM.pdf (518 kb)
Supplementary material 1 (PDF 518 kb)

References

  1. 1.
    Mayo SC, Pawlik TM (2009) Current management of colorectal hepatic metastasis. Expert Rev Gastroenterol Hepatol 3:131–144CrossRefPubMedGoogle Scholar
  2. 2.
    Shah A, Alberts S, Adam R (2008) Accomplishments in 2007 in the management of curable metastatic colorectal cancer. Gastrointest Cancer Res 2:S13–S18PubMedPubMedCentralGoogle Scholar
  3. 3.
    Leporrier J, Maurel J, Chiche L et al (2006) A population-based study of the incidence, management and prognosis of hepatic metastases from colorectal cancer. Br J Surg 93:465–474CrossRefPubMedGoogle Scholar
  4. 4.
    Ito K, Govindarajan A, Ito H et al (2010) Surgical treatment of hepatic colorectal metastasis: evolving role in the setting of improving systemic therapies and ablative treatments in the 21st century. Cancer J 16:103–110CrossRefPubMedGoogle Scholar
  5. 5.
    Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108CrossRefPubMedGoogle Scholar
  6. 6.
    D’Angelica M, Kornprat P, Gonen M et al (2011) Effect on outcome of recurrence patterns after hepatectomy for colorectal metastases. Ann Surg Oncol 18:1096–1103CrossRefPubMedGoogle Scholar
  7. 7.
    Abdalla EK, Vauthey JN, Ellis LM et al (2004) Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818–825 (discussion 825–827) CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Biasco G, Derenzini E, Grazi G et al (2006) Treatment of hepatic metastases from colorectal cancer: many doubts, some certainties. Cancer Treat Rev 32:214–228CrossRefPubMedGoogle Scholar
  9. 9.
    Parks R, Gonen M, Kemeny N et al (2007) Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: analysis of data from two continents. J Am Coll Surg 204:753–761 (discussion 761–763) CrossRefPubMedGoogle Scholar
  10. 10.
    Fong Y, Fortner J, Sun RL et al (1999) Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 230:309–318 (discussion 318–321) CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Halama N, Michel S, Kloor M et al (2011) Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 71:5670–5677CrossRefPubMedGoogle Scholar
  12. 12.
    Katz SC, Bamboat ZM, Maker AV et al (2013) Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol 20:946–955CrossRefPubMedGoogle Scholar
  13. 13.
    Nakagawa K, Tanaka K, Homma Y et al (2015) Low infiltration of peritumoral regulatory T cells predicts worse outcome following resection of colorectal liver metastases. Ann Surg Oncol 22:180–186CrossRefPubMedGoogle Scholar
  14. 14.
    Maker AV, Ito H, Mo Q et al (2015) Genetic evidence that intratumoral T-cell proliferation and activation are associated with recurrence and survival in patients with resected colorectal liver metastases. Cancer Immunol Res 3:380–388CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964CrossRefPubMedGoogle Scholar
  16. 16.
    Galon J, Fridman WH, Pages F (2007) The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res 67:1883–1886CrossRefPubMedGoogle Scholar
  17. 17.
    Galon J, Mlecnik B, Bindea G et al (2014) Towards the introduction of the ‘Immunoscore’ in the classification of malignant tumours. J Pathol 232:199–209CrossRefPubMedGoogle Scholar
  18. 18.
    Galon J, Pages F, Marincola FM et al (2012) Cancer classification using the Immunoscore: a worldwide task force. J Transl Med 10:205CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Galon J, Pages F, Marincola FM et al (2012) The immune score as a new possible approach for the classification of cancer. J Transl Med 10:1CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Van Cutsem E, Cervantes A, Nordlinger B et al (2014) Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):i1–i9CrossRefGoogle Scholar
  21. 21.
    Galon J, Fox BA, Bifulco CB et al (2016) Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. J Transl Med 14:273CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Pages F, Kirilovsky A, Mlecnik B et al (2009) In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol 27:5944–5951CrossRefPubMedGoogle Scholar
  23. 23.
    Pages F, Berger A, Camus M et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666CrossRefPubMedGoogle Scholar
  24. 24.
    Gabrielson A, Wu Y, Wang H et al (2016) Intratumoral CD3 and CD8 T-cell densities associated with relapse-free survival in HCC. Cancer Immunol Res 4:419–430CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Galon J, Costes A, Sanchez-Cabo F et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964CrossRefPubMedGoogle Scholar
  26. 26.
    Ward-Hartstonge KA, McCall JL, McCulloch TR et al (2017) Inclusion of BLIMP-1+ effector regulatory T cells improves the Immunoscore in a cohort of New Zealand colorectal cancer patients: a pilot study. Cancer Immunol Immunother 66:515–522CrossRefPubMedGoogle Scholar
  27. 27.
    Katz SC, Pillarisetty V, Bamboat ZM et al (2009) T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol 16:2524–2530CrossRefPubMedGoogle Scholar
  28. 28.
    Brunner SM, Kesselring R, Rubner C et al (2014) Prognosis according to histochemical analysis of liver metastases removed at liver resection. Br J Surg 101:1681–1691CrossRefPubMedGoogle Scholar
  29. 29.
    Brudvik KW, Henjum K, Aandahl EM et al (2012) Regulatory T-cell-mediated inhibition of antitumor immune responses is associated with clinical outcome in patients with liver metastasis from colorectal cancer. Cancer Immunol Immunother 61:1045–1053CrossRefPubMedGoogle Scholar
  30. 30.
    Nakagawa K, Tanaka K, Homma Y et al (2015) Low infiltration of peritumoral regulatory T cells predicts worse outcome following resection of colorectal liver metastases. Ann Surg Oncol 22:180–186CrossRefPubMedGoogle Scholar
  31. 31.
    Nakagawa K, Tanaka K, Homma Y et al (2015) Low infiltration of peritumoral regulatory T cells predicts worse outcome following resection of colorectal liver metastases. Ann Surg Oncol 22:180–186CrossRefPubMedGoogle Scholar
  32. 32.
    Halama N, Michel S, Kloor M et al (2011) Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res 71:5670–5677CrossRefPubMedGoogle Scholar
  33. 33.
    Mlecnik B, Bindea G, Kirilovsky A et al (2016) The tumor microenvironment and Immunoscore are critical determinants of dissemination to distant metastasis. Sci Transl Med 8:326r–327rCrossRefGoogle Scholar
  34. 34.
    Shinto E, Hase K, Hashiguchi Y et al (2014) CD8+ and FOXP3+ tumor-infiltrating T cells before and after chemoradiotherapy for rectal cancer. Ann Surg Oncol 21(3):S414–S421CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Yun Wang
    • 1
    • 2
  • Hao-cheng Lin
    • 1
    • 2
  • Ma-yan Huang
    • 1
    • 3
  • Qiong Shao
    • 1
    • 4
  • Zhi-qiang Wang
    • 1
    • 2
  • Feng-hua Wang
    • 1
    • 2
  • Yun-fei Yuan
    • 1
    • 5
  • Bin-kui Li
    • 1
    • 5
  • De-shen Wang
    • 1
    • 2
  • Pei-rong Ding
    • 1
    • 6
  • Gong Chen
    • 1
    • 6
  • Xiao-jun Wu
    • 1
    • 6
  • Zhen-hai Lu
    • 1
    • 6
  • Li-ren Li
    • 1
    • 6
  • Zhi-zhong Pan
    • 1
    • 6
  • Peng Sun
    • 1
    • 3
  • Shu-mei Yan
    • 1
    • 3
  • De-sen Wan
    • 1
    • 6
  • Rui-hua Xu
    • 1
    • 2
    Email author
  • Yu-hong Li
    • 1
    • 2
    Email author
  1. 1.State Key Laboratory of Oncology in South ChinaSun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer MedicineGuangzhouPeople’s Republic of China
  2. 2.Department of Medical OncologySun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  3. 3.Department of PathologySun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  4. 4.Department of Molecular DiagnosticsSun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  5. 5.Department of Hepatobiliary SurgerySun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China
  6. 6.Department of Colorectal SurgerySun Yat-sen University Cancer CenterGuangzhouPeople’s Republic of China

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