Clinical Significance Of Chemokine CXCL9,10,11 And CXCR3 In Immunotherapy Monitoring Of Patients With Advanced NSCLC

Objective:At present,immunotherapy has been widely used in the first-line treatment of non-small cell lung cancer(Non-small Cell Lung Cancer,NSCLC),but the response of individuals to immunotherapy is very different,so it is very important to screen the markers with predictive performance.The purpose of this study is to detect the levels and dynamic changes of CXCR3,CXCL9,10 and 11 in peripheral serum of patients with NSCLC before and after anti-PD-1(programmed cell death-1)treatment,and to statistically analyze their clinical significance and the relationship between them and the efficacy of immunotherapy,in order to find new predictive markers for the efficacy of tumor immunotherapy,so as to provide better guidance for clinical practice.Methods:The peripheral blood of 38 patients with advanced NSCLC who received anti-PD-1immunotherapy in Bethune Hospital of Shanxi Province were collected before and after treatment.The concentrations of CXCL9,10,11 and CXCR3 were detected by ELISA method.According to the efficacy evaluation,the patients were divided into disease control group(Disease Control Rate,DCR)and disease progression group(Diseaseprogression,PD).The correlation of CXCL9,10,11 and CXCR3 with the efficacy and prognosis of immunotherapy was analyzed.Statistical analysis was carried out by using SPSS26.0software,and the difference was statistically significant.Results:1.Among the 38 NSCLC patients included,there were 28 males(73.7%),10females(26.3%),24 patients less than 65 years old(63.2%),14 cases more than 65 years old(36.8%),24 cases with smoking history(63.2%)and 14 cases who never smoked(36.8%).There were 20 cases of lung adenocarcinoma(52.6%),16 cases of squamous cell carcinoma(42.1%),2 cases of other types of lung cancer(5.2%),including 1 case of sarcomatoid carcinoma and 1 case of adenosquamous carcinoma,11 cases of stage Ⅲ(28.9%),27 cases of stage IV(71.1%),29 cases of physical status score(PS)1 case(76.3%),8 cases of 2 points(21.1%)and 1 case of 3 points(2.6%).There were 18 patients with lymph node metastasis(47.4%),20 patients without lymph node metastasis(52.6%),5 patients with brain metastasis(13.2%),33 patients without brain metastasis(86.8%),22 patients with distant metastasis(57.9%)and 16 patients without distant metastasis(42.1%).There were 6 patients with PD-L1 expression < 1%(15.8%),15 patients with 1-49%(39.5%),14 patients with more than 50%(44.7%),18 patients(44.4%)received singledrug immunotherapy,20 patients(52.6%)received Combination therapy.10 patients(26.3%)had adverse immune reactions,including 5 patients(13.1%)with immune-related pneumonia,4 patients with immune-related skin toxicity(10.5%),1 patient with immune hypothyroidism(11%),1 patient with immune-related osteoarthritis(11%)and 1 patient with immune-related enteritis(11%).Of all the patients who received anti-PD-1 treatment,15(39.5%)were SD,14(36.8%)and PR,9(23.7%)were PD patients.The median PFS time of all patients was 248 days.2.38 patients with advanced NSCLC were divided into DCR group(including SD,n= 15,PR,n = 14)and PD group(n = 9)according to the efficacy evaluation.The relationship between different efficacy groups and clinical characteristics was analyzed.The results showed that lymph node metastasis was significantly related to the short-term efficacy of immunotherapy(P < 0.05).3.The results showed that the levels of CXCL9,CXCL11 and CXCR3 increased after immunotherapy(P > 0.05),while CXCL10 decreased(P > 0.05),but there was no statistical significance.4.The initial serum levels of chemokine CXCL9 and 10 in DCR group were significantly higher than those in PD group.There was no statistical difference in other CXCL11 and CXCR3.At the first evaluation,the level of CXCL9 in DCR group was significantly higher than that in PD group,and the difference was statistically significant(P< 0.05).There was no significant difference in other CXCL10,11 and CXCR3.5.Comparing the change rate of serum chemokine level(initial level-initial level / initial level)of patients in different treatment groups,the change rate of CXCL9 in DCR group was signifi cantly higher than that in PD group,and the difference was statistically significant.The change rates of other chemokines and CXCR3 increased and decreased during anti-PD-1immunotherapy,but there was no significant difference among different therapeuti c groups(P > 0.05).6.Spearman rank correlation analysis showed that there was a positive correlation between chemokines and CXCR3 before and after treatment,and the correlation between CXCL10 and CXCL11 was the highest before treatment(r = 0.770,P <0.05).After treatment,the correlation between CXCL10 and CXCL11 was the highest.(r = 0.884,P <0.05).7.Using the ROC curve to evaluate the ability of chemokine to predict the efficacy of immunotherapy,the area under the CXCL9 curve was the highest(AUC value was89%),the sensitivity was 96.6%,and the specificity was 66.7%.The AUC value of the combination of the four chemokines(85%)was slightly lower than that of CXCL9,and the difference was statistically significant(P < 0.05).There was no significant difference in CXCL10,11 and CXCR3.8.Logistic regression analysis showed that the change rate of CXCL9,lymph node metastasis and the efficacy of treatment were correlated with the increase of CXCL9 level after treatment and the absence of lymph node metastasis.The increase of CXCL9 level and the absence of lymph node metastasis were independent influencing factors of disease control in patients with advanced NSCLC who received anti-PD-1 therapy.9.The ROC curve was used to predict the effect of immunotherapy on the change rate of CXCL9,and the cutoff value of CXCL9 change rate was 1.85%.According to this,the CXCL9 change rate group was divided into high change rate group and low change rate group.The survival curve of Kaplan-Meier was compared between the two groups.PFS in the high change rate group was significantly longer than that in the low change rate group.Conclusion:1.The level of CXCL9 is closely related to the response of anti-PD-1treatment,and is expected to become a biomarker to predict th e efficacy and prognosis of anti-PD-1 treatment in patients with advanced NSCLC.2.The baseline level of CXCL10 may be related to reactivity.3.Combined detection of CXCL9,10,11 and CXCR3 can improve the specificity of predicting the effica cy of immunotherapy.