Tumor-infiltrating macrophages can predict favorable prognosis in hepatocellular carcinoma after resection

  • Yi-Wei Li
  • Shuang-Jian Qiu
  • Jia Fan
  • Qiang Gao
  • Jian Zhou
  • Yong-Sheng Xiao
  • Yang Xu
  • Xiao-Ying Wang
  • Jian Sun
  • Xiao-Wu Huang
Original Paper

Abstract

Purpose

To evaluate the prognostic value of tumor-associated macrophages (TAM), individually or synergistically with CD45RO + memory T cells (TM), in hepatocellular carcinoma (HCC) patients following resection.

Methods

The infiltration of TAM and TM was assessed by immunohistochemistry in tissue microarray containing 302 HCC specimens. Correlations between TAM/TM infiltration and clinicopathologic features, disease-free survival (DFS) and overall survival (OS) were statistically analyzed.

Results

High TAM infiltration was associated with both improved DFS (P = 0.0021) and OS (P = 0.0481). Multivariate analysis identified TAM infiltration as independent prognostic factor for DFS (P = 0.004) and OS (P = 0.049). A second analysis clarified the synergistic effect of TAM&TM infiltration for DFS (P = 0.004) and OS (P = 0.040).

Conclusions

Both TAM infiltration alone and concomitant infiltration of TAM&TM are associated with improved DFS/OS, suggesting that TAM could protect HCC patients from recurrence/metastasis and prolong survival by distinct mechanisms.

Keywords

Tumor-associated macrophages (TAM) CD45RO + T cell (TMHepatocellular carcinoma (HCC) Prognosis 

Abbreviations

HCC

Hepatocellular carcinoma

TAM

Tumor-associated macrophages

TM

CD45RO + T cell

TNM

Tumor-node-metastasis

TACE

Transcatheter arterial chemoembolization

OS

Overall survival

DFS

Disease-free survival

AFP

Alpha-fetoprotein

Supplementary material

432_2008_469_MOESM1_ESM.doc (82 kb)
Electronic supplementary material Appendix Table 5 and 6 (DOC 82 kb)

References

  1. Abe K, Harada M, Tamada K et al (1998) Early-appearing tumor-infiltrating natural killer cells play an important role in the nitric oxide production of tumor-associated macrophages through their interferon production. Cancer Immunol Immunother 45:225–233PubMedCrossRefGoogle Scholar
  2. Blankenstein T, Qin ZH, Uberla K et al (1991) Tumor suppression after tumor cell targeted tumor necrosis factor α gene transfer. J Exp Med 173:1047–1052PubMedCrossRefGoogle Scholar
  3. Bolat F, Kayaselcuk F, Nursal TZ et al (2006) Microvessel density, VEGF expression, and tumor-associated macrophages in breast tumors: correlations with prognostic parameters. J Exp Clin Cancer Res 25:365–372PubMedGoogle Scholar
  4. Bonta IL, Ben-Efraim S (1993) Involvement of inflammatory mediators in macrophage antitumor activity. J Leukoc Biol 54:613–626PubMedGoogle Scholar
  5. Bortolami M, Venturi C, Giacomelli L et al (2002) Cytokine, infiltrating macrophage and T cell-mediated response to development of primary and secondary human liver cancer. Dig Liver Dis 34:794–801PubMedCrossRefGoogle Scholar
  6. Brigati C, Noonan DM, Albini A et al (2002) Tumors and inflammatory infiltrates: friends or foes? Clin Exp Metastasis 19:247–258PubMedCrossRefGoogle Scholar
  7. Budhu A, Forgues M, Ye QH et al (2006) Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10:99–111PubMedCrossRefGoogle Scholar
  8. Cai XY, Gao Q, Qiu SJ et al (2006) Dendritic cell infiltration and prognosis of human hepatocellular carcinoma. J Cancer Res Clin Oncol 132:293–301PubMedCrossRefGoogle Scholar
  9. Chu CS, Woo EY, Toll AJ et al (2002) Tumor-associated macrophages as a source of functional dendritic cells in ovarian cancer patients. Clin Immunol 102:291–301PubMedCrossRefGoogle Scholar
  10. De Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37PubMedCrossRefGoogle Scholar
  11. Dunn GP, Old LJ, Schreiber RD (2004) The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137–148PubMedCrossRefGoogle Scholar
  12. Forssell J, Oberg A, Henriksson ML et al (2007) High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 13:1472–1479PubMedCrossRefGoogle Scholar
  13. Galarneau H, Villeneuve J, Gowing G et al (2007) Increased glioma growth in mice depleted of macrophages. Cancer Res 67:8874–8881PubMedCrossRefGoogle Scholar
  14. 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 313:1960–1964PubMedCrossRefGoogle Scholar
  15. Gao Q, Qiu SJ, Fan J et al (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 25:2586–2593PubMedCrossRefGoogle Scholar
  16. Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP- 9–expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114:623–633PubMedGoogle Scholar
  17. Hock H, Dorsch M, Kunzendorf U et al (1993) Mechanisms of rejection induced by tumor cell-targeted gene transfer of interleukin 2, interleukin 4, interleukin 7, tumor necrosis factor, or interferon gamma. Proc Natl Acad Sci USA 90:2774–2778PubMedCrossRefGoogle Scholar
  18. Jewell AP (2005) Is the liver an important site for the development of immune tolerance to tumors? Med Hypothesis 64:751–754CrossRefGoogle Scholar
  19. Langrish CL, McKenzie BS, Wilson NJ et al (2004) IL–12 and IL–23: master regulators of innate and adaptive immunity. Immunol Rev 202:96–105PubMedCrossRefGoogle Scholar
  20. Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612PubMedCrossRefGoogle Scholar
  21. Lin CY, Lin CJ, Chen KH et al (2006) Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction. FEBS Lett 580:3042–3050PubMedCrossRefGoogle Scholar
  22. Liotta LA (2001) An attractive force in metastasis. Nature 410:24–25PubMedCrossRefGoogle Scholar
  23. Lissbrant IF, Stattin P, Wikstrom P et al (2000) Tumor associated macrophages in human prostate cancer: relation to clinicopathological variables and survival. Int J Oncol 17:445–451PubMedGoogle Scholar
  24. Macmicking J, Xie QW, Nathan C (1997) Nitric oxide and macrophage function. Annu Rev Immunol 15:323–350PubMedCrossRefGoogle Scholar
  25. Michie CA, McLean A, Alcock C et al (1992) Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature 360:264–265PubMedCrossRefGoogle Scholar
  26. Murdoch C, Giannoudis A, Lewis CE (2004) Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 104:2224–2234PubMedCrossRefGoogle Scholar
  27. Ohno S, Inagawa H, Dhar D et al (2003) The degree of macrophage infiltration into cancer cell nest is a significant predictor of survival in gastric cancer patients. Anticancer Res 23:5015–5022PubMedGoogle Scholar
  28. Ohno S, Inagawa H, Soma G et al (2002) Role of tumor-associated macrophage in malignant tumors: should the location of the infiltrated macrophages be taken into account during evaluation? Anticancer Res 22:4269–4275PubMedGoogle Scholar
  29. Ohno S, Ohno Y, Suzuki N et al (2004) Correlation of histological localization of tumor-associated macrophages with clinicopathological features in endometrial cancer. Anticancer Res 24:3335–3342PubMedGoogle Scholar
  30. Pages F, Berger A, Camus M et al (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353:2654–2666PubMedCrossRefGoogle Scholar
  31. Parkin DM, Bray F, Ferlay J et al (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  32. Peng SH, Deng H, Yang JF et al (2005) Significance and relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma tissues. World J Gastroenterol 11:6521–6524PubMedGoogle Scholar
  33. Pollard JW (2004) Tumor-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78PubMedCrossRefGoogle Scholar
  34. Prendergast GC, Jaffee EM (2007) Cancer immunologists and cancer biologists: why we didn’t talk then but need to now. Cancer Res 67:3500–3504PubMedCrossRefGoogle Scholar
  35. Racanelli V, Rehermann B (2006) The liver as an immunological organ. Hepatology 43:S54–S62PubMedCrossRefGoogle Scholar
  36. Sica A, Schioppa T, Mantovani A et al (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727PubMedCrossRefGoogle Scholar
  37. Taskinen M, Karjalainen-Lindsberg ML, Nyman H et al (2007) A high tumor- associated macrophage content predicts favorable outcome in follicular lymphoma patients treated with rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone. Clin Cancer Res 13:5784–5789PubMedCrossRefGoogle Scholar
  38. Tsutsui S, Yasuda K, Suzuki K et al (2005) Macrophage infiltration and its prognostic implications in breast cancer: the relationship with VEGF expression and microvessel density. Oncol Rep 14:425–431PubMedGoogle Scholar
  39. Unitt E, Marshall A, Gelson W et al (2006) Tumour lymphocytic infiltrate and recurrence of hepatocellular carcinoma following liver transplantation. J Hepatol 45:246–253PubMedCrossRefGoogle Scholar
  40. Varotti G, Ramacciato G, Ercolani G et al (2005) Comparison between the fifth and sixth editions of the AJCC/UICC TNM staging systems for hepatocellular carcinoma: multicentric study on 393 cirrhotic resected patients. Eur J Surg Oncol 3:760–767CrossRefGoogle Scholar
  41. Yakirevich E, Resnick MB (2007) Regulatory T lymphocytes: pivotal components of the host antitumor response. J Clin Oncol 25:2586–2593CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Yi-Wei Li
    • 1
  • Shuang-Jian Qiu
    • 1
  • Jia Fan
    • 1
  • Qiang Gao
    • 1
  • Jian Zhou
    • 1
  • Yong-Sheng Xiao
    • 1
  • Yang Xu
    • 1
  • Xiao-Ying Wang
    • 1
  • Jian Sun
    • 1
  • Xiao-Wu Huang
    • 1
  1. 1.Liver Cancer Institute, Zhong Shan Hospital and Institutes of Biomedical Sciences, Shanghai Medical SchoolFudan UniversityShanghaiPeople’s Republic of China

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