| Objectives To determine whether CXC chemokine receptor-4(CXCR4)is a marker of prognosis and immune therapy in patients with lung squamous cell carcinoma(LUSC)based on The Cancer Genome Atlas(TCGA)database.The potential use of CXCR4antagonists in patients with lung squamous cell carcinoma were investigated.A retrospective analysis of CXCR4 protein expression in the prognostic impact of LUSC patients treated with immune checkpoint inhibitors(ICIs)was further analyzed.Methods Information on stage I-II LUSC patients(n=400)and LUSC paracancer samples(n=49)were obtained based on the TCGA database.From January 1,2019 to December 31,2020,clinical and pathological data of patients with ICIs-containing LUSC(n=72)diagnosed by the Department of Pathology of the Hebei General Hospital were retrospectively analyzed.Immunohistochemistry was used to determine CXCR4 protein expression.Statistical analysis was performed using v4.0.3 R software,SPSS 25.0 and Graphpad Prism 8.0.2 software.Results 1 Based on the median CXCR4 expression,patients with early LUSC were split into two groups:high and low CXCR4 expression,according to the TCGA database.The relationship between the different CXCR4 expression groups and the clinical characteristics of patients with early LUSC was investigated,and statistically significant differences were found only between CXCR4 and survival outcome(P=0.048)and gender(P=0.039).Although the disease-specific survival(DSS)of the two groups with high and low CXCR4 expression was not statistically significant(HR=0.636,95%CI:0.377-1.075,P=0.0908),survival analysis suggested a trend for the low CXCR4expression group to have a better DSS,while the high CXCR4 expression group had a worse overall survival(OS)than the low CXCR4 expression group(HR=0.712,95%CI:0.518-0.979,P=0.0365).CXCR4 was analyzed for correlation with 27 epithelial mesenchymal transition(EMT)and 17 cytokine genes,and was found to be positively correlated with the vast majority of genes involved in boosting EMT occurrence and negatively correlated with EMT suppressor genes,and positively correlated with most immunosuppressive and inflammatory cytokines.The relationship between CXCR4 and eight immune checkpoint markers,tumor mutation burden(TMB)and Tumor Immune Dysfunction and Exclusion(TIDE)scores revealed that CXCR4 was upregulated in the high expression group compared to the low expression group at all immune checkpoint markers,as well as finding that CXCR4 expression was positively correlated with immune checkpoints and negatively correlated with TMB,and that the TIDE scores were higher in the high CXCR4 expression group compared to the low CXCR4 expression group.These findings imply that in early LUSC,immunotherapy is less effective in the high CXCR4-expressing group.In early LUSC,TIMER algorithm examination of the association between CXCR4 and immune cells revealed that the high CXCR4 expression group had a higher abundance of B cells,CD4~+T cells,CD8~+T cells,neutrophils,macrophages,and myeloid dendritic cells compared to the low expression group.2 In a retrospective study of 72 LUSC patients receiving ICIs-containing LUSC,a positive CXCR4 protein expression rate of 61.11%was identified in cancer tissues from LUSC patients.Independent of other factors,the difference between CXCR4 protein expression and the clinical stage was statistically significant(χ~2=6.538,P=0.048)and was positively correlated(r=0.289).According to the Log-rank test,the CXCR4 negative group was likely to have a longer progression free survival(PFS)(8.2 months vs.5.8 months P=0.041)and longer OS(17.3 months vs.10.6 months,P<0.001)than the CXCR4positive group.Stratified analysis among clinical stages and different lines of treatment for ICIs show that PFS were longer in the CXCR4 negative group than in the CXCR4-positive group,all P-value were<0.05 except for stage III LUSC patients’P-value was 0.052,while OS was all longer in the CXCR4 negative group than in the CXCR4 positive group(P<0.05).Univariate analysis showed that patients PFS was associated with clinical stages(P<0.001),different line treatment of ICIs(P=0.008),and CXCR4 protein expression(P=0.041),while patients’OS was associated with the degree of differentiation of the cancer tissue(P=0.023),clinical stage(P<0.001),line treatment of ICIs(P=0.005),peripheral blood lymphocyte expression(P=0.003),and CXCR4protein expression(P<0.001).The results of the multifactorial analysis showed that clinical stages(P=0.011)and lines of treatment for ICIs(P=0.018)were independent factors affecting patients’PFS,while degrees of differentiation(P=0.022),clinical stages(P<0.001),different lines of treatment for ICIs(P=0.035),CXCR4 protein expression(P=0.008)were independent factors influencing patients’OS.Conclusions 1 CXCR4 was able to predict survival prognosis in early LUSC patients,according to the TCGA database,and was linked to cytokines and tumor-infiltrating immune cells in EMT.CXCR4 may play a role in immune evasion and could be used to predict the success of immunotherapy.CXCR4 antagonists may be a novel therapeutic medication option for individuals with early LUSC,and early treatment of CXCR4antagonists may reduce recurrence rates and mortality in patients with early LUSC.2According to the findings of a retrospective study showing a positive correlation between CXCR4 and the clinical stage of patients,CXCR4 expression may be a predictor of the efficacy of ICIs and a prognostic indicator for patients with LUSC treated with ICIs.Figure 15;Table 6;Reference 137... |
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