Prediction and Prognosis Analysis for Immunotherapy of Intra-tumoral Chemokines CCR1, CXCR6, and CXCL9 in Advanced Lung Adenocarcinoma

Objective Constructing a chemokine model to predict immune checkpoint blockade (ICB) efficacy and prognosis in advanced lung adenocarcinoma (LUAD).

Methods A total of 42 advanced LUAD patients (training cohort) who underwent ICB were retrospectively collected from the data of the previous study. We obtained transcriptome sequencing data from tumor tissues before ICB treatment. Screening for chemokines that significantly affect the efficacy of ICB treatment and the survival prognosis of patients with advanced LUAD by bioinformatics methods, and the efficacy was evaluated by progression-free disease (PFS), and the prognosis was evaluated by overall survival (OS). Transcriptome sequencing and survival-related data of 25 cases of non-small cell lung cancer (NSCLC) were downloaded from the Gene Expression Omnibus (GEO) database dataset (GSE 135222) and identified as a validation cohort.

Results Through univariate Cox regression analysis, nine chemokines significantly associated with favorable OS in advanced LUAD patients were screened, among which patients with high expression of CCR1, CXCR6, and CXCL9 had significantly longer OS. A risk model based on the expression of these three chemokines could be constructed. Survival analysis results show that risk score was negatively correlated with patients’ PFS and OS, which means advanced LUAD patients with low risk (risk score ≤ −1.33) could benefit more from ICB treatment. The median PFS in the low-risk group was 19.7 months, whereas in the high-risk group (risk score > −1.33) was 2.9 months 95% confidence interval (CI) 0.12~0.51, P < 0.001, and the median OS in the high-risk group was 6.0 months, while it was not reached in the low-risk group (95%CI 0.08~0.38, P < 0.001). The results from the GEO dataset confirmed the association between the risk score and PFS. Patients were classified as low-risk based on the risk score (risk score ≤ −1.85) were associated with a longer median PFS of 2.7 months, whereas the high-risk group (risk score > −1.85) had a shorter median PFS of 1.2 months (95%CI 0.12~0.93, P = 0.009).

Conclusions The high expression of CCR1, CXCR6, and CXCL9 indicates that patients with advanced LUAD have a low risk of disease progression, which is associated with favorable PFS and OS, and may provide a novel perspective for the adjuvant setting of ICB therapy for advanced LUAD patients.