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Tumor-Associated Macrophage Infiltration in Colorectal Cancer Liver Metastases is Associated With Better Outcome

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

Abstract

Background

Tumor-associated macrophages (TAMs) support growth in most human cancers, with the notable exception of colorectal adenocarcinoma, in which TAM infiltration of primary tumors is correlated with a better outcome. The importance of TAMs in colorectal liver metastases (CLM) is unknown.

Methods

Using a tissue microarray of CLM resected at their institution from 1998 to 2000, the authors quantified immune marker expression by immunohistochemistry (IHC) using Metamorph Image Analysis software. Findings showed that CD68, CD3, CD4, CD8, FoxP3, and MHC-I were correlated with overall survival (OS) and disease-free survival (DFS).

Results

Tumor cores from 158 patients were analyzed. The median follow-up period was 117 months for survivors (n = 39). The univariate analysis showed a significant positive association between DFS and CD4+ (p = 0.025) and CD68+ (p = 0.007). The findings showed a significant positive correlation of OS with CD4+ (p = 0.042), whereas the correlation with CD68+ was not significant (p = 0.17). Cutoffs were determined to dichotimize each marker for the highest log-rank statistic. Patients with CD4high had a median OS of 115 months and DFS of 41 months (p = 0.007 compared with 40 and 16 months, respectively, for patients with CD4low (p = 0.022). Patients with CD68high had a median OS of 50 months and a median DFS of 25 months (p = 0.67) compared with 43 and 15 months (p = 0.028). In the multivariate analysis of factors affecting DFS, high CD68 was associated with longer DFS (hazard ratio [HR], 0.63, 95% confidence interval [CI], 0.43–0.94; p = 0.02), independently of clinicopathologic variables and CD4.

Conclusions

High TAM infiltration in resected CLM is associated with better outcome, independently of known clinicopathologic and immune predictors. This suggests that TAM depletion, which is being tested clinically in other cancers, may be detrimental in CLM.

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References

  1. Erreni M, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) and inflammation in colorectal cancer. Cancer Microenviron. 2011;4:141–54.

    Article  CAS  PubMed  Google Scholar 

  2. Heusinkveld M, van der Burg SH. Identification and manipulation of tumor-associated macrophages in human cancers. J Translat Med. 2011;9:216.

    Article  CAS  Google Scholar 

  3. Cavnar MJ, Zeng S, Kim TS, et al. KIT oncogene inhibition drives intratumoral macrophage M2 polarization. J Exp Med. 2013;210:2873–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhang QW, Liu L, Gong CY, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PloS ONE. 2012;7:e50946.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Bacman D, Merkel S, Croner R, Papadopoulos T, Brueckl W, Dimmler A. TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study. BMC Cancer. 2007;7:156.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R. High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res.2007;13:1472–9.

    Article  CAS  PubMed  Google Scholar 

  7. Khorana AA, Ryan CK, Cox C, Eberly S, Sahasrabudhe DM. Vascular endothelial growth factor, CD68, and epidermal growth factor receptor expression and survival in patients with stage II and stage III colon carcinoma: a role for the host response in prognosis. Cancer. 2003;97:960–8.

    Article  PubMed  Google Scholar 

  8. Tan SY, Fan Y, Luo HS, Shen ZX, Guo Y, Zhao LJ. Prognostic significance of cell infiltrations of immunosurveillance in colorectal cancer. World J Gastroenterol. 2005;11:1210–14.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhou Q, Peng RQ, Wu XJ, et al. The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Translat Med. 2010;8:13.

    Article  Google Scholar 

  10. Mlecnik B, Tosolini M, Kirilovsky A, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29:610–18.

    Article  PubMed  Google Scholar 

  11. Naito Y, Saito K, Shiiba K, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58:3491–4.

    CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. Pages F, Kirilovsky A, Mlecnik B, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009;27:5944–51.

    Article  CAS  PubMed  Google Scholar 

  14. Prall F, Duhrkop T, Weirich V, et al. Prognostic role of CD8+ tumor-infiltrating lymphocytes in stage III colorectal cancer with and without microsatellite instability. Hum Pathol. 2004;35:808–16.

    Article  CAS  PubMed  Google Scholar 

  15. 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.

    Article  PubMed  Google Scholar 

  16. Katz SC, Bamboat ZM, Maker AV, et al. Regulatory T cell infiltration predicts outcome following resection of colorectal cancer liver metastases. Ann Surg Oncol. 2013;20:946–55.

    Article  PubMed  Google Scholar 

  17. 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.

    Article  PubMed  Google Scholar 

  18. Turcotte S, Katz SC, Shia J, et al. Tumor MHC class I expression improves the prognostic value of T-cell density in resected colorectal liver metastases. Cancer Immunol Res. 2014;2:530–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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. discussion 318–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mann CD, Metcalfe MS, Leopardi LN, Maddern GJ. The clinical risk score: emerging as a reliable preoperative prognostic index in hepatectomy for colorectal metastases. Arch Surg. 2004;139:1168–72.

    Article  PubMed  Google Scholar 

  21. Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27:872–7.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. DeNardo DG, Brennan DJ, Rexhepaj E, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discovery. 2011;1:54–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer. 2016;2:15025.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Beatty GL, Chiorean EG, Fishman MP, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011;331:1612–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dolcetti R, Viel A, Doglioni C, et al. High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol. 1999;154:1805–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. Haddad R, Ogilvie RT, Croitoru M, et al. Microsatellite instability as a prognostic factor in resected colorectal cancer liver metastases. Ann Surg Oncol. 2004;11:977–82.

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Murray PJ, Allen JE, Biswas SK, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41:14–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ohtani H, Naito Y, Saito K, Nagura H. Expression of costimulatory molecules B7-1 and B7-2 by macrophages along invasive margin of colon cancer: a possible antitumor immunity? Lab Invest. 1997;77:231–41.

    CAS  PubMed  Google Scholar 

  32. Sugita J, Ohtani H, Mizoi T, et al. Close association between Fas ligand (FasL; CD95L)-positive tumor-associated macrophages and apoptotic cancer cells along invasive margin of colorectal carcinoma: a proposal on tumor-host interactions. Jpn J Cancer Res Gann. 2002;93:320–8.

    Article  CAS  PubMed  Google Scholar 

  33. Funada Y, Noguchi T, Kikuchi R, Takeno S, Uchida Y, Gabbert HE. Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncol Rep. 2003;10:309–13.

    PubMed  Google Scholar 

  34. Bailey C, Negus R, Morris A, et al. Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis. 2007;24:121–30.

    Article  CAS  PubMed  Google Scholar 

  35. Taylor CR, Levenson RM. Quantification of immunohistochemistry: issues concerning methods, utility, and semiquantitative assessment II. Histopathology. 2006;49:411–24.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Irina Linkov from the Pathology Core Facility for performing the IHC, and Yevgeniy Romin from the Molecular Cytology Core Facility for assisting with the digital imaging and automated quantification.

Conflict of interest

There are no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Michael J. Cavnar MD, Peter J. Allen MD, Vinod P. Balachandran MD, Michael I. D’Angelica MD, T. Peter Kingham MD, William R. Jarnagin MD & Ronald P. DeMatteo MD

  2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Jinru Shia MD

  3. Department of Surgery, Centre hospitalier de l’Université de Montréal, Montreal, QC, Canada

    Simon Turcotte MD, MSc

  4. Department of Surgery, Roger Williams Medical Center, Providence, RI, USA

    Steven C. Katz MD

  5. Department of Surgery, Boston University School of Medicine, Boston, MA, USA

    Steven C. Katz MD

  6. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Deborah Kuk ScM & Mithat Gönen PhD

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  1. Michael J. Cavnar MD
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  2. Simon Turcotte MD, MSc
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Corresponding author

Correspondence to Ronald P. DeMatteo MD.

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Cavnar, M.J., Turcotte, S., Katz, S.C. et al. Tumor-Associated Macrophage Infiltration in Colorectal Cancer Liver Metastases is Associated With Better Outcome. Ann Surg Oncol 24, 1835–1842 (2017). https://doi.org/10.1245/s10434-017-5812-8

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  • DOI: https://doi.org/10.1245/s10434-017-5812-8

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