Abstract
Background
The role of tumour-associated macrophages (TAMs) in predicting the prognosis of colorectal cancer (CRC) remains controversial. This is especially so because the prognostic significance and clinicopathological relevance of different subtypes of TAMs in the immune microenvironment of CRC have not yet been established.
Objective
To assess the clinicopathological and prognostic value of pan-macrophages, M1-macrophages or M2-macrophages in patients with CRC.
Methods
Comprehensive searched on the Medline/PubMed, Web of Science (WoS) and Google Scholar databases was conducted to identify relevant studies published up to April 2019. The association between overall survival (OS), cancer-specific survival (CSS) or disease-free survival (DFS) and TAMs was analysed by meta-analysis.
Results
A total of 3749 patients from 17 studies were included. The pooled hazard ratios (HRs) indicated that high-density pan-macrophages improved OS (HR 0.67, P = 0.02). The pooled HR for M2-macrophages showed that high M2-macrophages infiltration was significantly associated with shorter OS (HR 2.93, P < 0.0001) and DFS (HR 2.04, P = 0.02). The pooled odds ratios (ORs) revealed that high-density TAMs was associated with high CD8+ T cell infiltration (OR 2.04, P = 0.007), no distant metastasis (NDM) (OR 0.38, P < 0.0001), microsatellite instability-high (MSI-H) (OR 0.38, P = 0.001), no lymph node metastasis (NLNM) (OR 0.54, P = 0.0002) and non-mucinous cancer (OR 0.39, P < 0.00001).
Conclusions
Unlike other solid tumours, high-density CD68+ macrophage infiltration can be a good prognostic marker for CRC. However, when macrophages act as targets of combination therapy in CRC treatment, this might be more effective for CRC patients with high CD8+ T cell infiltrate, NDM, MSI-H, NLNM and non-mucinous cancer.
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References
Algars A et al (2012) Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients. Int J Cancer 131:864–873. https://doi.org/10.1002/ijc.26457
Alves AM, Diel LF, Lamers ML (2018) Macrophages and prognosis of oral squamous cell carcinoma: a systematic review. J Oral Pathol Med 47:460–467. https://doi.org/10.1111/jop.12643
Atarashi K et al (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science (New York, NY) 331:337–341. https://doi.org/10.1126/science.1198469
Bacman D, Merkel S, Croner R, Papadopoulos T, Brueckl W, Dimmler A (2007) 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 7:156. https://doi.org/10.1186/1471-2407-7-156
Bailey C et al (2007) Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis 24:121–130. https://doi.org/10.1007/s10585-007-9060-3
Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125:5591–5596. https://doi.org/10.1242/jcs.116392
Banerjee A, Chabria Y, Kanna NRR, Gopi J, Rowlo P, Sun XF, Pathak S (2019) Role of tumor specific niche in colon cancer progression and emerging therapies by targeting tumor microenvironment. Adv Exp Med Biol. https://doi.org/10.1007/5584_2019_355
Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896. https://doi.org/10.1038/ni.1937
Biswas SK et al (2006) A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107:2112–2122. https://doi.org/10.1182/blood-2005-01-0428
Bohn T et al (2018) Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol 19:1319–1329. https://doi.org/10.1038/s41590-018-0226-8
Cavnar MJ et al (2017) Tumor-associated macrophage infiltration in colorectal cancer liver metastases is associated with better outcome. Ann Surg Oncol 24:1835–1842. https://doi.org/10.1245/s10434-017-5812-8
Chaput N et al (2013) Tumour-infiltrating CD68 + and CD57 + cells predict patient outcome in stage II-III colorectal cancer. Br J Cancer 109:1013–1022. https://doi.org/10.1038/bjc.2013.362
Colegio OR et al (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563. https://doi.org/10.1038/nature13490
de Ruiter EJ, Ooft ML, Devriese LA, Willems SM (2017) The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. Oncoimmunology 6:e1356148. https://doi.org/10.1080/2162402x.2017.1356148
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:e47045. https://doi.org/10.1371/journal.pone.0047045
Fleetwood AJ, Dinh H, Cook AD, Hertzog PJ, Hamilton JA (2009) GM-CSF- and M-CSF-dependent macrophage phenotypes display differential dependence on type I interferon signaling. J Leukoc Biol 86:411–421. https://doi.org/10.1189/jlb.1108702
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 13:1472–1479. https://doi.org/10.1158/1078-0432.ccr-06-2073
Franklin RA et al (2014) The cellular and molecular origin of tumor-associated macrophages. Science (New York, NY) 344:921–925. https://doi.org/10.1126/science.1252510
Fu Q et al (2019) Prognostic value of tumor-infiltrating lymphocytes in melanoma: a systematic review and meta-analysis. Oncoimmunology 8:1593806. https://doi.org/10.1080/2162402x.2019.1593806
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. Oncology Rep 10:309–313
Galon J, Bruni D (2019) Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov 18:197–218. https://doi.org/10.1038/s41573-018-0007-y
Giraudo E, Inoue M, Hanahan D (2004) An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J Clin Invest 114:623–633. https://doi.org/10.1172/jci22087
Gonzalez H, Hagerling C, Werb Z (2018) Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev 32:1267–1284. https://doi.org/10.1101/gad.314617.118
Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964. https://doi.org/10.1038/nri1733
Grossman JG et al (2018) Recruitment of CCR1(+) tumor associated macrophage to sites of liver metastasis confers a poor prognosis in human colorectal cancer. Oncoimmunology 7:e1470729. https://doi.org/10.1080/2162402x.2018.1470729
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-beta 1 expression and patients’ survival. J Mol Histol 44:679–692. https://doi.org/10.1007/s10735-013-9520-9
Hagemann T et al (2008) “Re-educating” tumor-associated macrophages by targeting NF-kappaB. J Exp Med 205:1261–1268. https://doi.org/10.1084/jem.20080108
Hao NB, Lu MH, Fan YH, Cao YL, Zhang ZR, Yang SM (2012) Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol 2012:948098. https://doi.org/10.1155/2012/948098
Hasita H et al (2010) Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci 101:1913–1919. https://doi.org/10.1111/j.1349-7006.2010.01614.x
Ivanov II et al (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498. https://doi.org/10.1016/j.cell.2009.09.033
Joshi S et al (2014) Rac2 controls tumor growth, metastasis and M1-M2 macrophage differentiation in vivo. PloS one 9:e95893. https://doi.org/10.1371/journal.pone.0095893
Kawachi A, Yoshida H, Kitano S, Ino Y, Kato T, Hiraoka N (2018) Tumor-associated CD204(+) M2 macrophages are unfavorable prognostic indicators in uterine cervical adenocarcinoma. Cancer Sci 109:863–870. https://doi.org/10.1111/cas.13476
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 97:960–968. https://doi.org/10.1002/cncr.11152
Kim Y, Wen XY, 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 73:663–671. https://doi.org/10.1111/his.13674
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 5:10. https://doi.org/10.1080/2162402x.2015.1106677
Lavin Y, Mortha A, Rahman A, Merad M (2015) Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol 15:731–744. https://doi.org/10.1038/nri3920
Le DT et al (2015) PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509–2520. https://doi.org/10.1056/nejmoa1500596
Le DT et al (2016) Programmed death-1 blockade in mismatch repair deficient colorectal cancer. J Clin Oncol 34:2. https://doi.org/10.1200/jco.2016.34.15_suppl.103
Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612. https://doi.org/10.1158/0008-5472.can-05-4005
Li S et al (2018) Tumor-associated macrophages remodeling EMT and predicting survival in colorectal carcinoma. Oncoimmunology 7:7. https://doi.org/10.1080/2162402x.2017.1380765
Li Y et al (2019) The prognostic and clinicopathological roles of PD-L1 expression in colorectal cancer: a systematic review and meta-analysis. Front Pharmacol 10:139. https://doi.org/10.3389/fphar.2019.00139
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686. https://doi.org/10.1016/j.it.2004.09.015
Mantovani A, Sica A, Allavena P, Garlanda C, Locati M (2009) Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. Hum Immunol 70:325–330. https://doi.org/10.1016/j.humimm.2009.02.008
Martinez FO, Sica A, Mantovani A, Locati M (2008) Macrophage activation and polarization. Front Biosci J Virtual Libr 13:453–461
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93:387–391. https://doi.org/10.1038/sj.bjc.6602678
Mei Z et al (2014) Tumour-infiltrating inflammation and prognosis in colorectal cancer: systematic review and meta-analysis. Br J Cancer 110:1595–1605. https://doi.org/10.1038/bjc.2014.46
Mlecnik B et al (2018) Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djx123
Murray PJ et al (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20. https://doi.org/10.1016/j.immuni.2014.06.008
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. https://doi.org/10.1186/1479-5876-5-62
Nandi B et al (2016) Stromal CCR1 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages. Oncoimmunology 5:e1189052. https://doi.org/10.1080/2162402x.2016.1189052
Noy R, Pollard JW (2014) Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61. https://doi.org/10.1016/j.immuni.2014.06.010
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 104:1236–1244. https://doi.org/10.1111/cas.12212
Pages F et al (2018) International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet (London, England) 391:2128–2139. https://doi.org/10.1016/s0140-6736(18)30789-x
Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78. https://doi.org/10.1038/nrc1256
Qian BZ, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51. https://doi.org/10.1016/j.cell.2010.03.014
Ruffell B, Affara NI, Coussens LM (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33:119–126. https://doi.org/10.1016/j.it.2011.12.001
Salama P, Phillips M, Grieu F, Morris M, Zeps N, Joseph D, Platell C, Iacopetta B (2009) Tumor-infiltrating FOXP3+ T regulatory cells show strong prognostic significance in colorectal cancer. J Clin Oncol 27:186–192
Schmieder A, Michel J, Schonhaar K, Goerdt S, Schledzewski K (2012) Differentiation and gene expression profile of tumor-associated macrophages. Semin Cancer Biol 22:289–297. https://doi.org/10.1016/j.semcancer.2012.02.002
Shabo I, Olsson H, Elkarim R, Sun XF, Svanvik J (2014) Macrophage infiltration in tumor stroma is related to tumor cell expression of CD163 in colorectal cancer. Cancer Microenviron 7:61–69. https://doi.org/10.1007/s12307-014-0145-7
Shibutani M et al (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 17:404. https://doi.org/10.1186/s12885-017-3395-1
Siegel RL, Miller KD, Jemal A (2019) Cancer statistics. CA Cancer J Clin 69:7–34. https://doi.org/10.3322/caac.21551
Sorensen MD, Dahlrot RH, Boldt HB, Hansen S, Kristensen BW (2018) Tumour-associated microglia/macrophages predict poor prognosis in high-grade gliomas and correlate with an aggressive tumour subtype. Neuropathol Appl Neurobiol 44:185–206. https://doi.org/10.1111/nan.12428
Srivastava K et al (2014) Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26:880–895. https://doi.org/10.1016/j.ccell.2014.11.005
Sugimura K et al (2015) High infiltration of tumor-associated macrophages is associated with a poor response to chemotherapy and poor prognosis of patients undergoing neoadjuvant chemotherapy for esophageal cancer. J Surg Oncol 111:752–759. https://doi.org/10.1002/jso.23881
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 11:1210–1214
Teng F et al (2016) Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR1 axis. J Hematol Oncol 9:8. https://doi.org/10.1186/s13045-015-0231-4
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. https://doi.org/10.1186/1745-6215-8-16
Vaupel P (2008) Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. Oncologist 13(Suppl 3):21–26. https://doi.org/10.1634/theoncologist.13-S3-21
Vlad C, Kubelac P, Fetica B, Vlad D, Irimie A, Achimas-Cadariu P (2015) The prognostic value of FOXP3+ T regulatory cells in colorectal cancer. J BUON 20:114–119
Wang B, Li Q, Qin L, Zhao S, Wang J, Chen X (2011) Transition of tumor-associated macrophages from MHC class II(hi) to MHC class II(low) mediates tumor progression in mice. BMC Immunol 12:43. https://doi.org/10.1186/1471-2172-12-43
Wei C et al (2019) Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer 18:64. https://doi.org/10.1186/s12943-019-0976-4
Xiong Y, Wang K, Zhou H, Peng L, You W, Fu Z (2018) Profiles of immune infiltration in colorectal cancer and their clinical significant: A gene expression-based study. Cancer Med 7:4496–4508. https://doi.org/10.1002/cam4.1745
Yahaya MAF, Lila MAM, Ismail S, Zainol M, Afizan N (2019) Tumour-associated macrophages (TAMs) in colon cancer and how to reeducate them. J Immunol Res 2019:2368249. https://doi.org/10.1155/2019/2368249
Yang L, Zhang Y (2017) Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol 10:58. https://doi.org/10.1186/s13045-017-0430-2
Yin SC et al (2017) The prognostic and clinicopathological significance of tumor-associated macrophages in patients with gastric cancer: a meta-analysis. PloS One 12:14. https://doi.org/10.1371/journal.pone.0170042
Yuan X, Zhang J, Li D, Mao Y, Mo F, Du W, Ma X (2017) Prognostic significance of tumor-associated macrophages in ovarian cancer: a meta-analysis. Gynecol Oncol 147:181–187. https://doi.org/10.1016/j.ygyno.2017.07.007
Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF (2011) Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma. Med Oncol (Northwood, London, England) 28:1447–1452. https://doi.org/10.1007/s12032-010-9638-5
Zhang QW et al (2012) Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PloS One 7:e50946. https://doi.org/10.1371/journal.pone.0050946
Zhang J et al (2016) High infiltration of tumor-associated macrophages influences poor prognosis in human gastric cancer patients, associates with the phenomenon of EMT. Medicine 95:e2636. https://doi.org/10.1097/md.0000000000002636
Zhou Q 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. https://doi.org/10.1186/1479-5876-8-13
Zigmond E et al (2012) Ly6C hi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37:1076–1090. https://doi.org/10.1016/j.immuni.2012.08.026
Acknowledgements
Our special acknowledgments to Mr. Xiang Zhou for helping us with editing.
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The study was funded by National Natural Science Foundation of China (No. 81472819, No. 81672342), the Zhejiang Provincial Natural Science Foundation of China (No. LY19H030012), the Fundamental Research Funds for the Central Universities (No. 2019QNA7028, No. 2019FZJD009).
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Zhao, Y., Ge, X., Xu, X. et al. Prognostic value and clinicopathological roles of phenotypes of tumour-associated macrophages in colorectal cancer. J Cancer Res Clin Oncol 145, 3005–3019 (2019). https://doi.org/10.1007/s00432-019-03041-8
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DOI: https://doi.org/10.1007/s00432-019-03041-8