Prognostic Value Of Tumor-infiltrating FOXP3~+ Regulatory T Cells In Non-Small Cell Lung Cancer: A Systematic Review And Meta-analysis

PURPOSE:Many types of immunosuppressive mechanisms have been reported in cancer patients in nowadays.Regulatory T cells(Tregs),which express the master control transcription factor forkhead box P3(FOXP3),are considered to play an important role in hampering antitumor immune response.But the role of FOXP3~+ Tregs in the prognosis of patients with non-small cell lung cancer remains controversial.We did a meta-analysis to evaluate the prognostic effect of FOXP3~+ Tregs in non-small cell lung cancer.METHEDS:PubMed,Embase and the Cochrane Library were searched to identify eligible studies.The retrieval period is from the buliding time of all databases to January 2016.To obtain the literature related to tumor infiltrating FOXP3~+ regulation of T cells,the two researchers screened the literature according to the inclusion criteria and exclusion criteria.The data were extracted and analyzed by Rev Man software.The pooled hazard ratios(HRs)with 95% confidence intervals(CIs)were calculated to investigate the association between FOXP3~+ Tregs and outcome of lung cancer patients.Heterogeneity tests,subgroupanalysis,sensitivity analysis and publication bias were also conducted.RESULTS:A total of 10 articles including 1,910 patients were enrolled into the meta-analysis.The pooled Hazard ratios(HRs)indicated high FOXP3~+ Tregs infiltration had a significant negative effect on overall survival(OS)and recurrence-free survival(RFS)[HR =1.38,95% confidence interval(CI): 1.14-1.66,P=0.0007 vs HR =1.42,95% CI: 1.26-1.61,P<0.00001].Furthermore,high relative proportion of FOXP3~+ to CD3~+ were associated with higher risk of recurrence(HR=1.66,95% CI 1.10-2.50,P = 0.02).To avoid high statistical heterogeneity,we applied a relatively conservative random effect model and found that tumor stage and distribution site might be the causes of the heterogeneity.TS could be noted as a worse prognostic factor(HR =1.53,95% CI 1.27 to 1.84,P<0.00001),without any heterogeneity.The associations between FOXP3~+ Tregs and clinicopathologic parameters are summarized.High expression of FOXP3~+ in Tregs was not associated with gender,pathology and lymph node,which had no statistically significant differences(P>0.05).CONCLUSION:Our meta-analysis therefore demonstrated that presence of high levels of FOXP3~+ Tregs in tumor stroma could be recognized as a negative prognostic factor for lung cancer patients,while FOXP3~+ Tregs in tumor nest or in tumor stroma and in tumor nest had no significant impact on the survival of lung cancers.In two enrolled studies,high relative proportion of FOXP3~+ to CD3~+ were associated with higher risk of recurrence.