Purpose Tumor-associated neutrophils (TAN) have been reported in a variety of malignancies. We conducted an up-to-date meta-analysis to evaluate the prognostic role of TAN in cancer. Method Pubmed, Embase and web of science databases were searched for studies published up to April 2013. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated. The impact of neutrophils localization and primary antibody were also assessed. Results A total of 3946 patients with various solid tumors from 20 studies were included. High density of intratumoral neutrophils were independently associated with unfavorable survival; the pooled HRs were 1.68 (95%CI: 1.36–2.07, I2 = 55.8%, p<0.001) for recurrence-free survival (RFS)/disease-free survival (DFS), 3.36 (95%CI: 2.08–5.42, I2 = 0%, p<0.001) for cancer-specific survival (CSS) and 1.66 (95%CI: 1.37–2.01, I2 = 70.5%, p<0.001) for overall survival (OS). Peritumoral and stromal neutrophils were not statistically significantly associated with survival. When grouped by primary antibody, the pooled HRs were 1.80 (95%CI: 1.47–2.22, I2 = 67.7%, p<0.001) for CD66b, and 1.44 (95%CI: 0.90–2.30, I2 = 45.9%, p = 0.125) for CD15, suggesting that CD66b positive TAN might have a better prognostic value than CD15. Conclusion High levels of intratumoral neutrophils are associated with unfavorable recurrence-free, cancer-specific and overall survival.
References
[1]
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144: 646–674. doi: 10.1016/j.cell.2011.02.013
[2]
Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454: 436–444. doi: 10.1038/nature07205
[3]
Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21: 309–322. doi: 10.1016/j.ccr.2012.02.022
[4]
Galdiero MR, Bonavita E, Barajon I, Garlanda C, Mantovani A, et al. (2013) Tumor associated macrophages and neutrophils in cancer. Immunobiology 218: 1402–1410. doi: 10.1016/j.imbio.2013.06.003
[5]
Donskov F, Bennedsgaard KM, Hokland M, Marcussen N, Fisker R, et al. (2004) Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma. Cancer Immunol Immunother 53: 729–739. doi: 10.1007/s00262-004-0525-9
[6]
Riesco A (1970) Five-year cancer cure: relation to total amount of peripheral lymphocytes and neutrophils. Cancer 25: 135–140. doi: 10.1002/1097-0142(197001)25:1<135::aid-cncr2820250120>3.0.co;2-9
[7]
Donskov F, von der Maase H (2006) Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol 24: 1997–2005. doi: 10.1200/jco.2005.03.9594
[8]
Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, et al. (2009) Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol 27: 4709–4717. doi: 10.1200/jco.2008.18.9498
[9]
Jensen TO, Schmidt H, Moller HJ, Donskov F, Hoyer M, et al. (2012) Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma. Cancer 118: 2476–2485. doi: 10.1002/cncr.26511
[10]
Rao HL, Chen JW, Li M, Xiao YB, Fu J, et al. (2012) Increased intratumoral neutrophil in colorectal carcinomas correlates closely with malignant phenotype and predicts patients' adverse prognosis. PLoS One 7: e30806. doi: 10.1371/journal.pone.0030806
[11]
Li YW, Qiu SJ, Fan J, Zhou J, Gao Q, et al. (2011) Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. J Hepatol 54: 497–505. doi: 10.1016/j.jhep.2010.07.044
[12]
Kuang DM, Zhao Q, Wu Y, Peng C, Wang J, et al. (2011) Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. J Hepatol 54: 948–955. doi: 10.1016/j.jhep.2010.08.041
[13]
Gao Q, Zhao YJ, Wang XY, Qiu SJ, Shi YH, et al. (2012) CXCR6 upregulation contributes to a proinflammatory tumor microenvironment that drives metastasis and poor patient outcomes in hepatocellular carcinoma. Cancer Res 72: 3546–3556. doi: 10.1158/0008-5472.can-11-4032
[14]
Zhou SL, Dai Z, Zhou ZJ, Wang XY, Yang GH, et al. (2012) Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma. Hepatology 56: 2242–2254. doi: 10.1002/hep.25907
[15]
Gu FM, Gao Q, Shi GM, Zhang X, Wang J, et al. (2012) Intratumoral IL-17(+) cells and neutrophils show strong prognostic significance in intrahepatic cholangiocarcinoma. Ann Surg Oncol 19: 2506–2514. doi: 10.1245/s10434-012-2268-8
[16]
Zhao JJ, Pan K, Wang W, Chen JG, Wu YH, et al. (2012) The prognostic value of tumor-infiltrating neutrophils in gastric adenocarcinoma after resection. PLoS One 7: e33655. doi: 10.1371/journal.pone.0033655
[17]
Ino Y, Yamazaki-Itoh R, Shimada K, Iwasaki M, Kosuge T, et al. (2013) Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br J Cancer 108: 914–923.
[18]
Trellakis S, Bruderek K, Dumitru CA, Gholaman H, Gu X, et al. (2010) Polymorphonuclear granulocytes in human head and neck cancer: enhanced inflammatory activity, modulation by cancer cells and expansion in advanced disease. Int J Cancer 129: 2183–2193. doi: 10.1002/ijc.25892
[19]
Caruso RA, Bellocco R, Pagano M, Bertoli G, Rigoli L, et al. (2002) Prognostic value of intratumoral neutrophils in advanced gastric carcinoma in a high-risk area in northern Italy. Mod Pathol 15: 831–837. doi: 10.1097/01.mp.0000020391.98998.6b
[20]
Carus A, Ladekarl M, Hager H, Pilegaard H, Nielsen PS, et al. (2013) Tumor-associated neutrophils and macrophages in non-small cell lung cancer: No immediate impact on patient outcome. Lung Cancer 81(1): 130–137. doi: 10.1016/j.lungcan.2013.03.003
[21]
Dumitru CA, Bankfalvi A, Gu X, Eberhardt WE, Zeidler R, et al. (2013) Neutrophils Activate Tumoral CORTACTIN to Enhance Progression of Orohypopharynx Carcinoma. Front Immunol 4: 33. doi: 10.3389/fimmu.2013.00033
[22]
Dumitru CA, Bankfalvi A, Gu X, Zeidler R, Brandau S, et al. (2013) AHNAK and inflammatory markers predict poor survival in laryngeal carcinoma. PLoS One 8: e56420. doi: 10.1371/journal.pone.0056420
[23]
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6: e1000097. doi: 10.1371/journal.pmed.1000097
[24]
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. doi: 10.1186/1745-6215-8-16
[25]
Nedergaard BS, Nielsen K, Nyengaard JR, Ladekarl M (2007) Stereologic estimation of the total numbers, the composition and the anatomic distribution of lymphocytes in cone biopsies from patients with stage I squamous cell carcinoma of the cervix uteri. APMIS 115: 1321–1330. doi: 10.1111/j.1600-0643.2007.00655.x
[26]
Chen LC, Wang LJ, Tsang NM, Ojcius DM, Chen CC, et al. (2012) Tumour inflammasome-derived IL-1beta recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma. EMBO Mol Med 4: 1276–1293. doi: 10.1002/emmm.201201569
[27]
Ilie M, Hofman V, Ortholan C, Bonnetaud C, Coelle C, et al. (2012) Predictive clinical outcome of the intratumoral CD66b-positive neutrophil-to-CD8-positive T-cell ratio in patients with resectable nonsmall cell lung cancer. Cancer 118: 1726–1737. doi: 10.1002/cncr.26456
[28]
Richards CH, Flegg KM, Roxburgh CSD, Going JJ, Mohammed Z, et al. (2012) The relationships between cellular components of the peritumoural inflammatory response, clinicopathological characteristics and survival in patients with primary operable colorectal cancer. British Journal of Cancer 106: 2010–2015.
[29]
Carus A, Ladekarl M, Hager H, Nedergaard BS, Donskov F (2013) Tumour-associated CD66b neutrophil count is an independent prognostic factor for recurrence in localised cervical cancer. Br J Cancer 108(10): 2116–2122.
[30]
Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, et al. (2012) Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One 7: e50946. doi: 10.1371/journal.pone.0050946
[31]
Castillo JJ, Dalia S, Shum H (2011) Meta-analysis of the association between cigarette smoking and incidence of Hodgkin's Lymphoma. J Clin Oncol 29: 3900–3906. doi: 10.1200/jco.2011.35.4449
[32]
Tazzyman S, Niaz H, Murdoch C (2013) Neutrophil-mediated tumour angiogenesis: subversion of immune responses to promote tumour growth. Semin Cancer Biol 23: 149–158. doi: 10.1016/j.semcancer.2013.02.003
[33]
Dumitru CA, Lang S, Brandau S (2013) Modulation of neutrophil granulocytes in the tumor microenvironment: mechanisms and consequences for tumor progression. Semin Cancer Biol 23: 141–148. doi: 10.1016/j.semcancer.2013.02.005
[34]
Tecchio C, Scapini P, Pizzolo G, Cassatella MA (2013) On the cytokines produced by human neutrophils in tumors. Semin Cancer Biol 23: 159–170. doi: 10.1016/j.semcancer.2013.02.004
[35]
Brandau S, Moses K, Lang S (2013) The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins? Semin Cancer Biol 23: 171–182. doi: 10.1016/j.semcancer.2013.02.007
[36]
Donskov F (2013) Immunomonitoring and prognostic relevance of neutrophils in clinical trials. Semin Cancer Biol 23(3): 200–207. doi: 10.1016/j.semcancer.2013.02.001
[37]
Kliiman K, Altraja A (2010) Predictors and mortality associated with treatment default in pulmonary tuberculosis. Int J Tuberc Lung Dis 14: 454–463.
[38]
Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, et al. (2010) Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304: 1684–1692. doi: 10.1001/jama.2010.1500
[39]
Murdoch C, Muthana M, Coffelt SB, Lewis CE (2008) The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8: 618–631. doi: 10.1038/nrc2444
[40]
Skubitz KM, Campbell KD, Skubitz AP (1996) CD66a, CD66b, CD66c, and CD66d each independently stimulate neutrophils. J Leukoc Biol 60: 106–117.
[41]
Phillips ML, Nudelman E, Gaeta FC, Perez M, Singhal AK, et al. (1990) ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex. Science 250: 1130–1132. doi: 10.1126/science.1701274
[42]
Jang TJ, Park JB, Lee JI (2013) The Expression of CD10 and CD15 Is Progressively Increased during Colorectal Cancer Development. Korean J Pathol 47: 340–347. doi: 10.4132/koreanjpathol.2013.47.4.340
[43]
Tori A, Harada A, Nakao A, Nonami T, Ito M, et al. (1995) Expression of sialyl Lewis(x) in hepatocellular carcinoma. Hepatogastroenterology 42: 939–943.
[44]
Carus A, Donskov F, Nielsen PS, Hager H, Nedergaard BS, et al.. (2014) Strong prognostic value of tumor-infiltrating neutrophils and lymphocytes assessed by automated digital image analysis in early stage cervical cancer: A comparator study with observer-assisted stereological assessments. J OncoPathology 2:1-9.
[45]
Egger M, Zellweger-Zahner T, Schneider M, Junker C, Lengeler C, et al. (1997) Language bias in randomised controlled trials published in English and German. Lancet 350: 326–329. doi: 10.1016/s0140-6736(97)02419-7
