Skip to main content

Advertisement

SpringerLink
Log in

Prognostic Value of Diametrically Polarized Tumor-Associated Macrophages in Renal Cell Carcinoma

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

Abstract

Background

As the most abundant tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) are significant for fostering tumor progression. CD68+ TAMs display diversely polarized programs comprising CD11c+ proinflammatory macrophages (M1) and CD206+ immunosuppressive macrophages (M2). The aim of this study was to determine the survival impact of diametrically polarized TAMs in clear-cell renal cell carcinoma (ccRCC) and their application to stratification of patients according to their prognostic values.

Methods

The study included 185 consecutive patients with ccRCC who underwent nephrectomy between 1999 and 2001. CD68+ total and diametrically polarized (CD11c+ M1 and CD206+ M2) TAM densities were assessed by immunohistochemistry, and the relationships with clinicopathologic features and prognosis were evaluated.

Results

Low CD11c+ TAM density and high CD206+ TAM density were associated with reduced cancer-specific survival (P = 0.043 and P = 0.017, respectively), whereas CD68+ TAM density only had borderline prognostic significance (P = 0.062). Furthermore, combined analysis of CD11c+ and CD206+ TAMs (CD11c/CD206 signature) had a better power to predict patients’ outcome (P = 0.010). Together with TNM stage, tumor necrosis, and performance status, CD11c/CD206 signature was an independent prognostic factor (P = 0.010). When applied to the University of California Integrated Staging System intermediate-/high-risk group for localized ccRCC, CD11c/CD206 signature could further distinguish patients with dismal prognosis (P = 0.004).

Conclusions

Intratumoral balance of diametrically polarized TAMs is a novel independent predictor for survival in patients with ccRCC. Tipping the balance toward an antitumoral phenotype might be a promising target of postoperative adjuvant therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 1996;335:865–75.

    Article  CAS  PubMed  Google Scholar 

  2. Figlin RA. Renal cell carcinoma: management of advanced disease. J Urol. 1999;161:381–6; discussion 386–7.

    Article  CAS  PubMed  Google Scholar 

  3. Sun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, et al. Prognostic factors and predictive models in renal cell carcinoma: a contemporary review. Eur Urol. 2011;60:644–61.

    Article  PubMed  Google Scholar 

  4. Zisman A, Pantuck AJ, Wieder J, Chao DH, Dorey F, Said JW, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol. 2002;20:4559–66.

    Article  PubMed  Google Scholar 

  5. Patard JJ, Kim HL, Lam JS, Dorey FJ, Pantuck AJ, Zisman A, et al. Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study. J Clin Oncol. 2004;22:3316–22.

    Article  PubMed  Google Scholar 

  6. De Palma M, Lewis CE. Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell. 2013;23:277–86.

    Article  PubMed  Google Scholar 

  7. Fridman WH, Pages F, Sautes-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12:298–306.

    Article  CAS  PubMed  Google Scholar 

  8. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11:723–37.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Falini B, Flenghi L, Pileri S, Gambacorta M, Bigerna B, Durkop H, et al. PG-M1: a new monoclonal antibody directed against a fixative-resistant epitope on the macrophage-restricted form of the CD68 molecule. Am J Pathol. 1993;142:1359–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Morris DL, Singer K, Lumeng CN. Adipose tissue macrophages: phenotypic plasticity and diversity in lean and obese states. Curr Opin Clin Nutr Metab Care. 2011;14:341–6.

    Article  PubMed  Google Scholar 

  11. Ito A, Suganami T, Yamauchi A, Degawa-Yamauchi M, Tanaka M, Kouyama R, et al. Role of CC chemokine receptor 2 in bone marrow cells in the recruitment of macrophages into obese adipose tissue. J Biol Chem. 2008;283:35715–23.

    Article  CAS  PubMed  Google Scholar 

  12. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med. 2009;15:914–20.

    Article  CAS  PubMed  Google Scholar 

  13. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  CAS  PubMed  Google Scholar 

  14. Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W, Xiong YQ, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol. 2008;26:2707–16.

    Article  PubMed  Google Scholar 

  15. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122:787–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–96.

    Article  CAS  PubMed  Google Scholar 

  17. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750–61.

    Article  CAS  PubMed  Google Scholar 

  18. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.

    Article  CAS  PubMed  Google Scholar 

  19. Senovilla L, Vacchelli E, Galon J, Adjemian S, Eggermont A, Fridman WH, et al. Trial watch: Prognostic and predictive value of the immune infiltrate in cancer. Oncoimmunology. 2012;1:1323–43.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Jensen TO, Schmidt H, Moller HJ, Hoyer M, Maniecki MB, Sjoegren P, et al. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage I/II melanoma. J Clin Oncol. 2009;27:3330–7.

    Article  PubMed  Google Scholar 

  21. Komohara Y, Hasita H, Ohnishi K, Fujiwara Y, Suzu S, Eto M, et al. Macrophage infiltration and its prognostic relevance in clear cell renal cell carcinoma. Cancer Sci. 2011;102:1424–31.

    Article  CAS  PubMed  Google Scholar 

  22. Medrek C, Ponten F, Jirstrom K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012;12:306.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF. Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma. Med Oncol. 2011;28:1447–52.

    Article  PubMed  Google Scholar 

  24. Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX, et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res. 2010;16:3420–30.

    Article  CAS  PubMed  Google Scholar 

  25. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjallman AH, Ballmer-Hofer K, Schwendener RA. Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer. 2006;95:272–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Priceman SJ, Sung JL, Shaposhnik Z, Burton JB, Torres-Collado AX, Moughon DL, et al. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood. 2010;115:1461–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, et al. A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem. 2007;282:35279–92.

    Article  CAS  PubMed  Google Scholar 

  28. Wu H, Perrard XD, Wang Q, Perrard JL, Polsani VR, Jones PH, et al. CD11c expression in adipose tissue and blood and its role in diet-induced obesity. Arterioscler Thromb Vasc Biol. 2010;30:186–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Hume DA. Macrophages as APC and the dendritic cell myth. J Immunol. 2008;181:5829–35.

    Article  CAS  PubMed  Google Scholar 

  30. Geissmann F, Gordon S, Hume DA, Mowat AM, Randolph GJ. Unravelling mononuclear phagocyte heterogeneity. Nat Rev Immunol. 2010;10:453–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Duluc D, Corvaisier M, Blanchard S, et al. Interferon-gamma reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor-associated macrophages. Int J Cancer. 2009;125:367–73.

    Article  CAS  PubMed  Google Scholar 

  32. Fong CH, Bebien M, Didierlaurent A, Nebauer R, Hussell T, Broide D, et al. An antiinflammatory role for IKKbeta through the inhibition of “classical” macrophage activation. J Exp Med. 2008;205:1269–76.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, 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 Central  PubMed  Google Scholar 

  34. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, 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 Central  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by grants from National Key Projects for Infectious Diseases of China (2012ZX10002-012 to J.X.), National Natural Science Foundation of China (31100629 to W.Z., 31270863 to J.X., 81372755 to Z.L.), Program for New Century Excellent Talents in University (NCET-13-0146 to J.X.), and Shanghai Rising-Star Program (13QA1400300 to J.X.). We thank Drs. Yumei Wen and Jianxin Gu (Shanghai Medical College, Fudan University) for helpful discussions, and Dr. Lingli Chen (Zhongshan Hospital, Fudan University) for technical assistance.

Author information

Authors and Affiliations

  1. Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China

    Le Xu MD, PhD, Huimin An MD, Guomin Wang MD & Zongming Lin MD

  2. Department of Urology, Ninth People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

    Yu Zhu MD, PhD

  3. Department of Pathology, Children’s Hospital, Fudan University, Shanghai, China

    Lian Chen MD

  4. Department of Immunology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Weijuan Zhang PhD

  5. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Jiejie Xu MD, PhD

  6. Key Laboratory of Glycoconjugate Research, MOH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Jiejie Xu MD, PhD

  7. Key Laboratory of Medical Molecular Virology, MOE & MOH, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

    Jiejie Xu MD, PhD

Authors
  1. Le Xu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Zhu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lian Chen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Huimin An MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weijuan Zhang PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guomin Wang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zongming Lin MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jiejie Xu MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zongming Lin MD or Jiejie Xu MD, PhD.

Additional information

Drs. Le Xu, Yu Zhu, and Lian Chen contributed equally to this work.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, L., Zhu, Y., Chen, L. et al. Prognostic Value of Diametrically Polarized Tumor-Associated Macrophages in Renal Cell Carcinoma. Ann Surg Oncol 21, 3142–3150 (2014). https://doi.org/10.1245/s10434-014-3601-1

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-014-3601-1

Keywords

Search

Navigation