Study On Predicting The Prognosis Of Immunocheckpoint Inhibitor Treated Lung Cancer Patients With Brain Metastasis By Neutrophil-to-lymphocyte Ratio

Objective:To investigate the feasibility of the biomarker peripheral blood neutrophil to lymphocyte ratio(NLR)to predict the prognosis of immune checkpoint inhibitors(ICIs)in the treatment of lung cancer patients with brain metastases,and to provide a theoretical foundation for ICIs therapy in patients with brain metastases.Methods:Patients with lung cancer who were treated at our hospital between January 2018 and December 2021 were chosen as research subjects.Patients’clinical data and postoperative paraffin specimens were collected and tracked.174 advanced lung cancer patients were divided into four groups based on whether they had brain metastases or had received ICIs.NLR-based survival analysis was performed,and intracranial response was evaluated.The ROC curve was used to determine the optimal NLR threshold prior to ICI treatment.The survival curve was drawn using the Kaplan-Meier method,and the Log-rank test was used to analyze the relationship between ICIs treatment and BMS and NLR,as well as the relationship between NLR level and OS and iPFS in BMS patients.Variables associated with OS and iPFS were calculated using univariate and multivariate COX proportional hazard regression models.In addition,HE staining was performed on paraffin specimens of 19 patients with lung cancer brain metastases,and immunohistochemical analysis of CD3 and CD8 cells in TIL was performed.The correlation between variables was determined by regression analysis,the survival curve was described by Kaplan-Meier method,and the relationship between CD3~+TIL,CD8~+TIL and tumor size and OS was analyzed by Log-rank test.Results:1.An increasing trend in NLR was observed in 74 patients with BMS and a stable change in NLR levels was observed in 100 patients without BMS.Meanwhile,the ROC curve of NLR to predict disease control status before receiving ICIs was analyzed to obtain the best cut-off value of NLR level(3.63 in the BMS group,2.51 in the group without brain metastases).Kaplan-Meier survival curve showed that ICIs could significantly prolong the overall survival of lung cancer patients with BMS whose peripheral blood NLR≤3.63(p=0.01).2.An examination of intracranial reactions in patients with lung cancer brain metastases revealed that ICIs treatment resulted in better intracranial reactions in patients with low peripheral blood NLR when compared to other groups,and could significantly prolong the intracranial progression-free survival of patients(p<0.05).3.Univariate COX regression analysis showed that small cell lung cancer(primary type)and high levels of peripheral blood NLR before ICIs treatment had a greater impact on iPFS.There was no significant correlation between OS and iPFS and gender,age,smoking,number of peripheral metastasized organs and different ICIs treatment methods and types.Multivariate COX regression analysis showed that the independent risk factors for OS and iPFS were both high levels of peripheral blood NLR before ICIs treatment.4.The immune microenvironment analysis of BMS revealed that TIL number was negativelycorrelatedwithintracranialtumorsize(CD3:r=-0.6007,p=0.0389;CD8:r=-0.8272,p=0.0032),and patients with higher CD3 and CD8~+TIL infiltration had longer survival(p<0.05).Conclusion:Patients with lung cancer who have brain metastases can benefit from ICIs treatment,and NLR level prior to ICIs treatment is correlated with OS and iPFS.Patients with NLR≤3.63 before ICIs treatment have longer OS and iPFS.It is proposed that NLR be used as a low-cost,widely available independent predictive biomarker.