Checkpoint inhibitors have been approved for the treatment of
non-small cell lung cancer (NSCLC). However, only a minority of patients demonstrate a durable clinical response. PD-L1 scoring is currently the only
biomarker measure routinely used to select patients for
immunotherapy, but its predictive accuracy is modest. The aim of our study was to evaluate a proteomic assay for the analysis of patient plasma in the context of
immunotherapy. Pretreatment plasma samples from 43 NSCLC patients who received anti-PD-(L)1
therapy were analyzed using a proximity extension assay (PEA) to quantify 92 different immune oncology-related
proteins. The
plasma protein levels were associated with clinical and histopathological parameters, as well as
therapy response and survival. Unsupervised hierarchical cluster analysis revealed two patient groups with distinct
protein profiles associated with high and low immune
protein levels, designated as "hot" and "cold". Further supervised cluster analysis based on T-cell activation markers showed that higher levels of T-cell activation markers were associated with longer progression-free survival (PFS) (p < 0.01). The analysis of single
proteins revealed that high plasma levels of CXCL9 and CXCL10 and low ADA levels were associated with better response and prolonged PFS (p < 0.05). Moreover, in an explorative response prediction model, the combination of
protein markers (CXCL9, CXCL10, IL-15, CASP8, and ADA) resulted in higher accuracy in predicting response than
tumor PD-L1 expression or each
protein assayed individually. Our findings demonstrate a proof of concept for the use of multiplex
plasma protein levels as a tool for anti-PD-(L)1 response prediction in NSCLC. Additionally, we identified
protein signatures that could predict the response to anti-PD-(L)1
therapy.