Annals of Surgical Oncology

, Volume 20, Issue 2, pp 697–702

Clinical Impact of Tumor-infiltrating Lymphocytes for Survival in Curatively Resected Stage IV Colon Cancer with Isolated Liver or Lung Metastasis

  • Won-Suk Lee
  • Myunghee Kang
  • Jeong-Heum Baek
  • Jae-Ik Lee
  • Seung Yeon Ha
Translational Research and Biomarkers
  • 639 Downloads

Abstract

Background

The most reliable prognostic factor to date is tumor, node, metastasis stage. However, prognostic significance of tumor-infiltrating lymphocytes (TILs) in curatively resected stage IV colon cancer with isolated liver or lung lesion has not been clarified. The aim of this study was to assess and compare the prognostic role of TILs in curatively resected stage IV colon cancers.

Methods

Immunohistochemistry was used to assess the densities of CD8+, CD45RO+, and FOXP3+ according to tumor sites (primary tumor, liver, and lung) from 79 stage IV colon cancers. These were evaluated for association with histopathologic features and patients’ overall survival (OS).

Results

Higher density of CD45RO+ at primary and metastatic sites was associated with better patient outcomes (P = 0.009 and 0.027, respectively). The estimated 3-year OS rates for high-density CD45RO+ at metastatic and primary sites was 82.6 and 62.4 %, respectively, compared to 60.8 and 27.1 % in low-density CD45RO+. In multivariate analysis, CD45RO+ at the colon primary site (P = 0.007; relative risk 0.108; 95 % confidence interval 0.021–0.546) was the strongest prognostic factor.

Conclusions

High density of CD45RO+ TILs showed independent prognostic significance for OS. This result may help to improve the prognostication of curatively resected stage IV colon cancer.

Supplementary material

10434_2012_2752_MOESM1_ESM.docx (1.7 mb)
Supplementary material 1 (DOCX 1728 kb)

References

  1. 1.
    Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 2005;55:10–30.PubMedCrossRefGoogle Scholar
  2. 2.
    South and West Cancer Intelligence Unit. Wessex colorectal audit: final report—5-year outcomes. Winchester: South and West Cancer Intelligence Unit; 2000.Google Scholar
  3. 3.
    Lee WS, Yun SH, Chun HK, et al. Pulmonary resection for metastases from colorectal cancer: prognostic factors and survival. Int J Colorectal Dis. 2007;22:699–704.PubMedCrossRefGoogle Scholar
  4. 4.
    Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309–18.PubMedCrossRefGoogle Scholar
  5. 5.
    Ohlsson B, Stenram U, Tranberg KG. Resection of colorectal liver metastases: 25-year experience. World J Surg. 1998;22:268–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg. 1995;19:59–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Steele G Jr, Bleday R, Mayer RJ, Lindblad A, Petrelli N, Weaver D. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: Gastrointestinal Tumor Study Group Protocol 6584. J Clin Oncol. 1991;9:1105–12.PubMedGoogle Scholar
  8. 8.
    Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. 2004;240:644–57.PubMedCrossRefGoogle Scholar
  9. 9.
    Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med. 2000;343:905–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Lee WS, Yun HR, Yun SH, et al. Treatment outcomes of hepatic and pulmonary metastases from colorectal carcinoma. J Gastroenterol Hepatol. 2008;23:e367–72.PubMedCrossRefGoogle Scholar
  11. 11.
    Adam R, de Haas RJ, Wicherts DA, et al. Concomitant extrahepatic disease in patients with colorectal liver metastases: when is there a place for surgery? Ann Surg. 2011;253:349–59.PubMedCrossRefGoogle Scholar
  12. 12.
    Aoki T, Umekita N, Tanaka S, Noda K, Warabi M, Kitamura M. Prognostic value of concomitant resection of extrahepatic disease in patients with liver metastases of colorectal origin. Surgery. 2008;143:706–14.PubMedCrossRefGoogle Scholar
  13. 13.
    Carpizo DR, Are C, Jarnagin W, et al. Liver resection for metastatic colorectal cancer in patients with concurrent extrahepatic disease: results in 127 patients treated at a single center. Ann Surg Oncol. 2009;16:2138–46.PubMedCrossRefGoogle Scholar
  14. 14.
    de Haas RJ, Wicherts DA, Adam R. Resection of colorectal liver metastases with extrahepatic disease. Dig Surg. 2008;25:461–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:18538–43.PubMedCrossRefGoogle Scholar
  17. 17.
    Overwijk WW. Breaking tolerance in cancer immunotherapy: time to ACT. Curr Opin Immunol. 2005;17:187–94.PubMedCrossRefGoogle Scholar
  18. 18.
    Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol. 2009;27:186–92.PubMedCrossRefGoogle Scholar
  19. 19.
    Koch M, Beckhove P, Op den Winkel J, et al. Tumor infiltrating T lymphocytes in colorectal cancer: tumor-selective activation and cytotoxic activity in situ. Ann Surg. 2006;244:986–92.PubMedCrossRefGoogle Scholar
  20. 20.
    Edge SB, Byrd DR, Compton CC, et al. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.Google Scholar
  21. 21.
    Chai SM, Zeps N, Shearwood AM, et al. Screening for defective DNA mismatch repair in stage II and III colorectal cancer patients. Clin Gastroenterol Hepatol. 2004;2:1017–25.PubMedCrossRefGoogle Scholar
  22. 22.
    Michel S, Benner A, Tariverdian M, et al. High density of FOXP3-positive T cells infiltrating colorectal cancers with microsatellite instability. Br J Cancer. 2008;99:1867–73.PubMedCrossRefGoogle Scholar
  23. 23.
    Lee WS, Park S, Lee WY, Yun SH, Chun HK. Clinical impact of tumor-infiltrating lymphocytes for survival in stage II colon cancer. Cancer. 2010;116:5188–99.PubMedCrossRefGoogle Scholar
  24. 24.
    Ling Y, Cao X, Yu Z, Ruan C. Circulating dendritic cells subsets and CD4+ Foxp3+ regulatory T cells in adult patients with chronic ITP before and after treatment with high-dose dexamethasome. Eur J Haematol. 2007;79:310–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Loddenkemper C, Schernus M, Noutsias M, Stein H, Thiel E, Nagorsen D. In situ analysis of FOXP3+ regulatory T cells in human colorectal cancer. J Transl Med. 2006;4:52.PubMedCrossRefGoogle Scholar
  26. 26.
    Katz SC, Pillarisetty V, Bamboat ZM, et al. T cell infiltrate predicts long-term survival following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2009;16:2524–30.PubMedCrossRefGoogle Scholar
  27. 27.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Gao Q, Qiu SJ, Fan J, et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007;25:2586–93.PubMedCrossRefGoogle Scholar
  29. 29.
    Pages F, Berger A, Camus M, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353:2654–66.PubMedCrossRefGoogle Scholar
  30. 30.
    Chew A, Salama P, Robbshaw A, et al. SPARC, FOXP3, CD8 and CD45 correlation with disease recurrence and long-term disease-free survival in colorectal cancer. PLoS One. 2011;6:e22047.PubMedCrossRefGoogle Scholar
  31. 31.
    Woodland DL, Kohlmeier JE. Migration, maintenance and recall of memory T cells in peripheral tissues. Nat Rev Immunol. 2009;9:153–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Lee HE, Chae SW, Lee YJ, et al. Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer. 2008;99:1704–11.PubMedCrossRefGoogle Scholar
  33. 33.
    Halama N, Michel S, Kloor M, et al. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res. 2011;71:5670–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8.PubMedCrossRefGoogle Scholar
  35. 35.
    Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.PubMedCrossRefGoogle Scholar
  37. 37.
    Bindea G, Mlecnik B, Fridman WH, Pages F, Galon J. Natural immunity to cancer in humans. Curr Opin Immunol. 2010;22:215–22.PubMedCrossRefGoogle Scholar
  38. 38.
    Camus M, Tosolini M, Mlecnik B, et al. Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res. 2009;69:2685–93.PubMedCrossRefGoogle Scholar
  39. 39.
    Nagaraj S, Gabrilovich DI. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res. 2008;68:2561–3.PubMedCrossRefGoogle Scholar

Copyright information

© Society of Surgical Oncology 2012

Authors and Affiliations

  • Won-Suk Lee
    • 1
  • Myunghee Kang
    • 2
  • Jeong-Heum Baek
    • 1
  • Jae-Ik Lee
    • 3
  • Seung Yeon Ha
    • 2
  1. 1.Department of SurgeryGil Medical Center, School of Medicine, Gachon UniversityIncheonKorea
  2. 2.Department of PathologyGil Medical Center, School of Medicine, Gachon UniversityIncheonKorea
  3. 3.Department of Thoracic SurgeryGil Medical Center, School of Medicine, Gachon UniversityIncheonKorea

Personalised recommendations