BACKGROUND

Current clinical biomarkers for the programmed cell death 1 (PD-1) blockade therapy are insufficient because they rely only on the tumor properties, such as programmed cell death ligand 1 expression frequency and tumor mutation burden. Identifying reliable, responsive biomarkers based on the host immunity is necessary to improve the predictive values.

METHODS

We investigated levels of plasma metabolites and T cell properties, including energy metabolism markers, in the blood of patients with non-small cell lung cancer before and after treatment with nivolumab (n= 55). Predictive values of combination markers statistically selected were evaluated by cross-validation and linear discriminant analysis on discovery and validation cohorts, respectively. Correlation between plasma metabolites and T cell markers was investigated.

RESULTS

The 4 metabolites derived from the microbiome (hippuric acid), fatty acid oxidation (butyrylcarnitine), and redox (cystine and glutathione disulfide) provided high response probability (AUC= 0.91). Similarly, a combination of 4 T cell markers, those related to mitochondrial activation (PPARγ coactivator 1 expression and ROS), and the frequencies of CD8+ PD-1 hi and CD4+ T cells demonstrated even higher prediction value (AUC= 0.96). Among the pool of selected markers, the 4 T cell markers were exclusively selected as the highest predictive combination, probably because of their linkage to the abovementioned metabolite markers. In a prospective validation set (n= 24), these 4 cellular markers showed a high accuracy rate for clinical responses of patients (AUC= 0.92).

CONCLUSION