The Relationship Between HHLA2 And LAG-3 Expression And Prognosis In Lung Cancer

Objective: To detect the expression and co-expression of Human endogenous retrovirus-H long terminal repeat associating protein 2(HHLA2)and Lymphoete activation gene 3(LAG-3)in lung cancer tissue and adjacent tissue,analyze its association with clinicopathological characteristics and effects on lung cancer prognosis,and explore the potential significance of HHLA2 and LAG-3 expression as clinical prognostic markers of lung cancer.Methods: According to the criteria of the research design,114 patients with lung cancer who were surgically resected and diagnosed by histopathology at the Second Affiliated Hospital of Nanhua University from December 2013 to December 2017 were selected as the study objects,and their clinicopathological data,follow-up data and paraffin embedded lung tissue samples were collected.Immunohistochemical SP method was employed to detect the expression levelof HHLA2 and LAG-3 in lung cancer tissue and adjacent tissue.Chi-square test or Fisher exact probability method was used to detect the correlation between HHLA2 and LAG-3 expression or co-expression and clinicopathological characteristics,and the correlation between HHLA2 and LAG-3expression was identified by Spearman rank correlation test analyse.According to the results of semi-quantitative scoring,the study subjects were divided into low expression group and high expression group.The Kaplan-Meier method was used to draw the survival curve to analyse the effects of HHLA2 and LAG-3 expression and co-expression on overall survival(OS)and disease free survival(DFS),then Cox regression analysis was used to comprehensively evaluate the effects of HHLA2 and LAG-3 expression and co-expression on the lung cancer prognosis.Results: In lung cancer tissue,the positive rate of HHLA2 expression was 82.5%(94/114).There was no significant difference of the HHLA2 expression with regard to gender,age,occupation,drinking,history of hypertension,history of diabetes,histological subtype,T stage,and distant metastasis(P>0.05).There was significant difference in smoking index(χ~2=7.917,P=0.005),lymph node metastasis(χ~2=7.321,P=0.007)and TNM clinical stage(χ~2=4.234,P=0.040).OS of the HHLA2 high expression group was significantly lower than that of the HHLA2 low expression group(HR=2.375,95%CI: 1.502-3.756,P=0.0014),and the same was true for DFS(HR=2.778,95%CI:1.807-4.287,P<0.0001).The positive rate of LAG-3 expression was57.9%(66/114).There was no significant difference of LAG-3 expression in gender,age,occupation,smoking index,drinking,history of hypertension,history of diabetes,T stage,and distant metastasis(P>0.05),there were statistical differences in histological subtype(χ~2=7.108,P=0.038),lymph node metastasis(χ~2=5.614,P=0.018)and TNM clinical stage(χ~2=4.862,P=0.027).OS and DFS in LAG-3 high expression group were significantly lower than that in the LAG-3 low expression group(HR=2.701,95%CI: 1.740-4.191,P<0.0001;HR=2.780,95%CI:1.816-4.255,P<0.0001).The positive rate of HHLA2 and LAG-3co-expression was 56.1%(64/114).The HHLA2 and LAG-3co-expression was statistical different in lymph node metastasis(χ~2=6.436,P=0.011),TNM clinical stage(χ~2=5.608,P=0.018),and there were no statistical significances in age,gender,occupation,histological subtype,smoking,drinking,history of hypertension,history of diabetes,T stage,and M stage(P>0.05).Log-rank test showed that the OS and DFS of the HHLA2 and LAG-3 co-expression group were significantly shorter than the other groups(HR=2.754,95%CI: 1.772-4.281,P<0.0001;HR=2.903,95%CI: 1.891-4.457,P<0.0001).The expression of HHLA2 and LAG-3in lung cancer tissue was positively correlated(r=0.670,P=0.000).Cox regression analysis showed that TNM clinical stage(HR=2.656,95%CI:1.524-4.627,P=0.001),HHLA2 and LAG-3 co-expression(HR=2.619,95%CI: 1.616-4.245,P=0.000)were independent prognostic factors of OS in lung cancer,that T stage(HR=2.366,95%CI: 1.330-4.208,P=0.003),HHLA2 and LAG-3 co-expression(HR=2.847,95%CI:1.787-4.537,P= 0.000)were independent prognostic factors of DFS in lung cancer.Conclusions:1.The high expression of HHLA2 in lung cancer is related with smoking index,lymph node metastasis and TNM clinical stage.The high expression of LAG-3 is related with histological subtypes,lymph node metastasis and TNM clinical stage.HHLA2 and LAG-3 co-expression is related with lymph node metastasis and TNM clinical stage.2.The expression of HHLA2 and LAG-3 in lung cancer tissue is positively correlated.3.TNM clinical staging,HHLA2 and LAG-3 co-expression are independent prognostic risk factors for lung cancer OS,T staging,HHLA2 and LAG-3 co-expression are independent prognostic risk factors for lung cancer DFS,HHLA2 high expression and LAG-3 high expression have no single effects on lung cancer OS and DFS.