Tumor-associated Neutrophils As A New Prognostic Factor In Cancer:a Systematic Review And Meta-analysis

Objective:In addition to cancer cells, a tumor lesion contains a number of recruited normal cells that contribute to the hallmarks of cancer by creating the tumor microenvironment. Stromal cells, blood vessels and infiltrating inflammatory cells are major components of the tumor microenvironment. A leukocyte infiltrate, comprising mast cells, T cells, natural killer (NK) cells, T-regulatory (T-regs) cells, myeloid derived suppressor cells (MDSC), tumor-associated macrophages (TAM) and tumor-associated neutrophils (TAN) are key participants of the tumor microenvironment where they can promote or inhibit cancer formation and development. Neutrophil granulocytes are the most abundant circulating leukocytes and represent the first line of immune defense against invading pathogens. In contrast to the well-characterized TAM, the role and characteristics of TAN in cancer are poorly defined and has until recently been considered negligible because of their short life span and fully differentiated phenotype. The first study to identify the presence of TAN by use of immunohistochemistry as an independent poor prognostic factor in humans and to incorporate TAN into a prognostic risk model based on established clinicopathological features was published in2006. Recently, the prognostic role of TAN has been associated with poor clinical outcome in several human cancers, most notably in renal cell carcinoma, melanoma, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, gastric, lung, and head and neck cancer. However, some studies showed that there has no relationship between TAN and clinical outcome. At present, there is no systematic review regarding the pronostic value of TAN. Therefore, we performed the first meta-analysis to evaluate the effect of TAN in patients with cancer.Methods:PubMed, Embase and Web of Science were used to search for original articles analyzing the prognostic value of TAN in human cancer. Last search was updated on25April2013, and no lower date limit was used. Inclusion and exclusion criteria were made before any meta-analysis of the data. Studies which meet the criteria would be indued into this meta-analysis. Data were extracted form studies to establish the database. Stata Statistical Software (version12.0Stata Corp., College Station, TX, USA) was used for all analyses in our analysis.Results:Totally3962potentially relevant studies for TAN and human cancer prognosis were identified after initial searches. A total of3946patients with various solid tumors from20studies were included. in our analysis, neutrophils were further classified into three groups according to the localizations of neutrophils within the tumor compartments:intratumoral, peritumoral, and stromal. High density of intratumoral neutrophils were independently associated with unfavorable survival. The pooled HRs were1.68(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) and1.66(95%CI:1.37-2.01,I2=70.5%,p<0.001) for overall survival (OS). However, peritumoral and stromal neutrophils were not statistically significantly associated with survival. In order to further research, the data were grouped by histology of cancer. The data showed that the prognostic role of TAN has been associated with short OS in hepatocellular carcinoma and cholangiocarcinoma, head and neck cancer, non-small cell lung cancer, renal cell carcinoma, and gastric carcinoma. When grouped by primary antibody, the pooled HRs were1.80(95%CI:1.47-2.22,12=67.7%, p<0.001) for CD66b, and1.44(95%CI:0.90-2.30,12=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. However, peritumoral and stromal neutrophils were not statistically significantly associated with survival. Tumor-associated neutrophils are expected to be a novel biomarker in cancer, since its prognostic value in patients with cancer. Although some research achievements was made, the role and characteristics of TAN in cancer formation and development was not clear. Further studies are recommended, examining the mechanism of the adverse prognostic significance of high level of TAN.