Skip to main content

Advertisement

SpringerLink
Log in

Tumor-associated macrophage infiltration and prognosis in colorectal cancer: systematic review and meta-analysis

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background

Tumor-associated macrophages (TAMs) are key components of colorectal cancer (CRC) microenvironment, but their role in CRC prognosis is not fully defined.

Objective

This study aimed to evaluate prognostic value of different types and distribution of TAMs in CRC.

Methods

Total 27 studies with 6115 patients were searched from PubMed and Embase and analyzed to determine the association between TAMs, including distinct TAM subsets and infiltration location, and CRC survival. The prognostic impact of TAMs on CRC was further stratified by tumor type and mismatch repair system (MMR) status.

Results

A pooled analysis indicated that high density of TAMs in CRC tissue was significantly associated with favorable 5-year overall survival (OS) but not with disease-free survival (DFS). CD 68+ TAM subset correlated with better 5-year OS, while neither CD68+NOS2+ M1 subset nor CD163+ M2 subset was correlated with 5-year OS. Increased CD68+ TAM infiltration in tumor stroma but not in tumor islet predicted improved 5-year OS. Stratification by tumor type and MMR status showed that in colon cancer or MMR-proficient CRC, elevated TAM density was associated with better 5-year OS.

Conclusions

High infiltration of CD68+ TAMs could be a favorable prognostic marker in CRC. Future therapies stimulating CD68+ TAM infiltration may be promising in CRC treatment.

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
Fig. 4

Similar content being viewed by others

Data availability

All data are available upon request.

Abbreviations

CI:

confidence interval

CRC:

colorectal cancer

DFS:

disease-free survival

HE:

hematoxylin-eosin

HR:

hazard ratio

IHC:

immunohistochemistry

MMR:

mismatch repair system

NOS:

Newcastle-Ottawa Scale

NOS2:

nitric oxide synthase 2

OS:

overall survival

TAMs:

tumor-associated macrophages

TI:

tumor islet

TS:

tumor stroma

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108

    Article  Google Scholar 

  2. Bockelman C, Engelmann BE, Kaprio T, Hansen TF, Glimelius B (2015) Risk of recurrence in patients with colon cancer stage II and III: a systematic review and meta-analysis of recent literature. Acta Oncol 54(1):5–16

    Google Scholar 

  3. Alwarthan HAM, Al Anazi MS, Parine NR, Bhat RS, Alamro G, Aljarbou F, Al-Daihan SK (2019) The expressional level of tankyrase-1 gene and its regulation in colorectal cancer in a Saudi population. Biocell 43(2):51–58

    CAS  Google Scholar 

  4. Koelzer VH, Dawson H, Andersson E, Karamitopoulou E, Masucci GV, Lugli A, Zlobec I (2015) Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome. Transl Res 166(2):207–217

    CAS  Google Scholar 

  5. Korehisa S, Oki E, Iimori M, Nakaji Y, Shimokawa M, Saeki H, Okano S, Oda Y, Maehara Y (2018) Clinical significance of programmed cell death-ligand 1 expression and the immune microenvironment at the invasive front of colorectal cancers with high microsatellite instability. Int J Cancer 142(4):822–832

    CAS  Google Scholar 

  6. Oh DY, Venook AP, Fong L (2015) On the verge: immunotherapy for colorectal carcinoma. J Natl Compr Cancer Netw 13(8):970–978

    CAS  Google Scholar 

  7. Signorini L, Delbue S, Ferrante P, Bregni M (2016) Review on the immunotherapy strategies against metastatic colorectal carcinoma. Immunotherapy 8(10):1245–1261

    CAS  Google Scholar 

  8. Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, Angell H, Fredriksen T, Lafontaine L, Berger A, Bruneval P, Fridman WH, Becker C, Pagès F, Speicher MR, Trajanoski Z, Galon J (2013) Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 39(4):782–795

    CAS  Google Scholar 

  9. Ostuni R, Kratochvill F, Murray PJ, Natoli G (2015) Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol 36(4):229–239

    CAS  Google Scholar 

  10. Koelzer VH, Canonica K, Dawson H, Sokol L, Karamitopoulou-Diamantis E, Lugli A, Zlobec I (2016) Phenotyping of tumor-associated macrophages in colorectal cancer: impact on single cell invasion (tumor budding) and clinicopathological outcome. Oncoimmunology 5(4):e1106677

    Google Scholar 

  11. Chaput N, Svrcek M, Auperin A, Locher C, Drusch F, Malka D, Taieb J, Goere D, Ducreux M, Boige V (2013) Tumour-infiltrating CD68+ and CD57+ cells predict patient outcome in stage II-III colorectal cancer. Br J Cancer 109(4):1013–1022

    CAS  Google Scholar 

  12. Forssell J, Oberg A, Henriksson ML, Stenling R, Jung A, Palmqvist R (2007) High macrophage infiltration along the tumor front correlates with improved survival in colon cancer. Clin Cancer Res 13(5):1472–1479

    CAS  Google Scholar 

  13. Funada Y, Noguchi T, Kikuchi R, Takeno S, Uchida Y, Gabbert HE (2003) Prognostic significance of CD8+ T cell and macrophage peritumoral infiltration in colorectal cancer. Oncol Rep 10(2):309–313

    Google Scholar 

  14. Herrera M, Herrera A, Dominguez G, Silva J, Garcia V, Garcia JM, Gomez I, Soldevilla B, Munoz C, Provencio M et al (2013) Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients. Cancer Sci 104(4):437–444

    CAS  Google Scholar 

  15. Shabo I, Olsson H, Sun XF, Svanvik J (2009) Expression of the macrophage antigen CD163 in rectal cancer cells is associated with early local recurrence and reduced survival time. Int J Cancer 125(8):1826–1831

    CAS  Google Scholar 

  16. Algars A, Irjala H, Vaittinen S, Huhtinen H, Sundstrom J, Salmi M, Ristamaki R, Jalkanen S (2012) Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients. Int J Cancer 131(4):864–873

    Google Scholar 

  17. Baeten CI, Castermans K, Hillen HF, Griffioen AW (2006) Proliferating endothelial cells and leukocyte infiltration as prognostic markers in colorectal cancer. Clin Gastroenterol Hepatol 4(11):1351–1357

    CAS  Google Scholar 

  18. Zlobec I, Minoo P, Terracciano L, Baker K, Lugli A (2011) Characterization of the immunological microenvironment of tumour buds and its impact on prognosis in mismatch repair-proficient and -deficient colorectal cancers. Histopathology 59(3):482–495

    Google Scholar 

  19. Yamauchi M, Lochhead P, Morikawa T, Huttenhower C, Chan AT, Giovannucci E, Fuchs C, Ogino S (2012) Colorectal cancer: a tale of two sides or a continuum? Gut 61(6):794–797

    Google Scholar 

  20. Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, Liao X, Waldron L, Hoshida Y, Huttenhower C, Chan AT, Giovannucci E, Fuchs C, Ogino S (2012) Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut 61(6):847–854

    CAS  Google Scholar 

  21. Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, Zhao YW, Wei YQ (2012) Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One 7(12):e50946

    CAS  Google Scholar 

  22. Bauer K, Michel S, Reuschenbach M, Nelius N, von Knebel DM, Kloor M (2011) Dendritic cell and macrophage infiltration in microsatellite-unstable and microsatellite-stable colorectal cancer. Familial Cancer 10(3):557–565

    Google Scholar 

  23. Xiao Y, Freeman GJ (2015) The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy. Cancer Discov 5(1):16–18

    CAS  Google Scholar 

  24. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605

    Google Scholar 

  25. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17(24):2815–2834

    CAS  Google Scholar 

  26. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8:16

    Google Scholar 

  27. Edin S, Wikberg ML, Dahlin AM, Rutegard J, Oberg A, Oldenborg PA, Palmqvist R (2012) The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One 7(10):e47045

    CAS  Google Scholar 

  28. Gulubova M, Ananiev J, Yovchev Y, Julianov A, Karashmalakov A, Vlaykova T (2013) The density of macrophages in colorectal cancer is inversely correlated to TGF-beta1 expression and patients' survival. J Mol Histol 44(6):679–692

    CAS  Google Scholar 

  29. How J, Brown JR, Saylor S, Rimm DL (2014) Macrophage expression of tartrate-resistant acid phosphatase as a prognostic indicator in colon cancer. Histochem Cell Biol 142(2):195–204

    CAS  Google Scholar 

  30. Illemann M, Laerum OD, Hasselby JP, Thurison T, Hoyer-Hansen G, Nielsen HJ, Christensen IJ (2014) Urokinase-type plasminogen activator receptor (uPAR) on tumor-associated macrophages is a marker of poor prognosis in colorectal cancer. Cancer Med 3(4):855–864

    CAS  Google Scholar 

  31. Inoue Y, Nakayama Y, Minagawa N, Katsuki T, Nagashima N, Matsumoto K, Shibao K, Tsurudome Y, Hirata K, Nagata N, Itoh H (2005) Relationship between interleukin-12-expressing cells and antigen-presenting cells in patients with colorectal cancer. Anticancer Res 25(5):3541–3546

    CAS  Google Scholar 

  32. Khorana AA, Ryan CK, Cox C, Eberly S, Sahasrabudhe DM (2003) 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 97(4):960–968

    Google Scholar 

  33. Kinouchi M, Miura K, Mizoi T, Ishida K, Fujibuchi W, Ando T, Yazaki N, Saito K, Shiiba K, Sasaki I (2011) Infiltration of CD14-positive macrophages at the invasive front indicates a favorable prognosis in colorectal cancer patients with lymph node metastasis. Hepatogastroenterology 58(106):352–358

    Google Scholar 

  34. Nagorsen D, Voigt S, Berg E, Stein H, Thiel E, Loddenkemper C (2007) Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. J Transl Med 5:62

    Google Scholar 

  35. Nebiker CA, Han J, Eppenberger-Castori S, Iezzi G, Hirt C, Amicarella F, Cremonesi E, Huber X, Padovan E, Angrisani B, Droeser RA, Rosso R, Bolli M, Oertli D, von Holzen U, Adamina M, Muraro MG, Mengus C, Zajac P, Sconocchia G, Zuber M, Tornillo L, Terracciano L, Spagnoli GC (2014) GM-CSF production by tumor cells is associated with improved survival in colorectal Cancer. Clin Cancer Res 20(12):3094–3106

    CAS  Google Scholar 

  36. Ohnishi K, Komohara Y, Saito Y, Miyamoto Y, Watanabe M, Baba H, Takeya M (2013) CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma. Cancer Sci 104(9):1237–1244

    CAS  Google Scholar 

  37. Richards CH, Flegg KM, Roxburgh CS, Going JJ, Mohammed Z, Horgan PG, McMillan DC (2012) The relationships between cellular components of the peritumoural inflammatory response, clinicopathological characteristics and survival in patients with primary operable colorectal cancer. Br J Cancer 106(12):2010–2015

    CAS  Google Scholar 

  38. Shibutani M, Maeda K, Nagahara H, Fukuoka T, Nakao S, Matsutani S, Hirakawa K, Ohira M (2017) The peripheral monocyte count is associated with the density of tumor-associated macrophages in the tumor microenvironment of colorectal cancer: a retrospective study. BMC Cancer 17(1):404

    Google Scholar 

  39. Tan SY, Fan Y, Luo HS, Shen ZX, Guo Y, Zhao LJ (2005) Prognostic significance of cell infiltrations of immunosurveillance in colorectal cancer. World J Gastroenterol 11(8):1210–1214

    Google Scholar 

  40. Zhou Q, Peng RQ, Wu XJ, Xia Q, Hou JH, Ding Y, Zhou QM, Zhang X, Pang ZZ, Wan DS et al (2010) The density of macrophages in the invasive front is inversely correlated to liver metastasis in colon cancer. J Transl Med 8:13

    Google Scholar 

  41. Cavnar MJ, Turcotte S, Katz SC, Kuk D, Gonen M, Shia J, Allen PJ, Balachandran VP, D'Angelica MI, Kingham TP et al (2017) Tumor-associated macrophage infiltration in colorectal cancer liver metastases is associated with better outcome. Ann Surg Oncol 24(7):1835–1842

    Google Scholar 

  42. Kim Y, Wen X, Bae JM, Kim JH, Cho NY, Kang GH (2018) The distribution of intratumoral macrophages correlates with molecular phenotypes and impacts prognosis in colorectal carcinoma. Histopathology 73(4):663–671

    Google Scholar 

  43. Li Z, Xu Z, Huang Y, Zhao R, Cui Y, Zhou Y, Wu X (2018) The predictive value and the correlation of peripheral absolute monocyte count, tumor-associated macrophage and microvessel density in patients with colon cancer. Medicine (Baltimore) 97(21):e10759

    CAS  Google Scholar 

  44. Ma J, Liu L, Che G, Yu N, Dai F, You Z (2010) The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time. BMC Cancer 10:112

    Google Scholar 

  45. Ohno S, Inagawa H, Dhar DK, Fujii T, Ueda S, Tachibana M, Suzuki N, Inoue M, Soma G, Nagasue N (2003) The degree of macrophage infiltration into the cancer cell nest is a significant predictor of survival in gastric cancer patients. Anticancer Res 23(6D):5015–5022

    Google Scholar 

  46. Nagtegaal ID, Marijnen CA, Kranenbarg EK, Mulder-Stapel A, Hermans J, van de Velde CJ, van Krieken JH (2002) Short-term preoperative radiotherapy interferes with the determination of pathological parameters in rectal cancer. J Pathol 197(1):20–27

    Google Scholar 

Download references

Acknowledgments

This project was supported by the Innovation Commission of Kunming University of Science and Technology (No. KKSY 201860009) and Foundation of Yunnan Provincial Science and Technology (Nos. 2017NS208, 2018NS0232, 2018NS0231).

Author information

Author notes

  1. Jinyuan Li and Linhai Li contribute equally to the article.

Authors and Affiliations

  1. Department of General Surgery I, The First People’s Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology,, No.157 Jinbi Road, Kunming, Yunnan, China

    Jinyuan Li, Linhai Li, Yuejin Li, Yaxin Long, Quan Zhao, Yiming Ouyang, Weimin Bao & Kunmei Gong

Authors
  1. Jinyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Linhai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuejin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yaxin Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Quan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yiming Ouyang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Weimin Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kunmei Gong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Jinyuan Li, Linhai Li, Yuejin Li, Yaxin Long, Yiming Ouyang, Quan Zhao, and Weimin Bao collected and analyzed the data. Kunmei Gong designed the study and wrote the manuscript.

Corresponding author

Correspondence to Kunmei Gong.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, J., Li, L., Li, Y. et al. Tumor-associated macrophage infiltration and prognosis in colorectal cancer: systematic review and meta-analysis. Int J Colorectal Dis 35, 1203–1210 (2020). https://doi.org/10.1007/s00384-020-03593-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-020-03593-z

Keywords

Search

Navigation