Plasma Proteomic Analysis in Non-Small Cell Lung Cancer Patients Treated with PD-1/PD-L1 Blockade

Abstract

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.

Longitudinal plasma proteomic profiling of patients with non-small cell lung cancer undergoing immune checkpoint blockade

“… 43 CXCL10 was identified as a biomarker for response as well. 44 In addition, previous studies have demonstrated an association between these two chemokines and resistance to therapy in patients with NSCLC. Oyanagi et al reported significantly lower baseline levels of CXCL8, CXCL10 and tumor necrosis factor-α and higher levels of follistatin in patients with durable response.…”

Phase 2 trial of T-cell activation using MVI-816 and pembrolizumab in patients with metastatic, castration-resistant prostate cancer (mCRPC)

“…CXCL9 and CXCL10 have previously been reported to be increased in plasma following treatment with PD-1 blockade in patients with non-small-cell lung cancer, and this was associated with longer PFS. 32 In the current trial, we found that, while CXCL9 and CXCL10 were increased after treatment, these were not associated with longer treatment time or rPFS. In contrast, increases in IFN-γ were, suggesting that T-cell activation, presumably by vaccination, which may be important to improving the efficacy Open access of 1 blockade.…”

Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells

“…In such testing, it is important to consider how genomic and proteomic data can be optimally paired to maximize potential predictive utility as gene expression of secretory proteins does not always translate to similar changes in protein expression, and vice versa 8,74 . For this reason, measuring circulating plasma protein measurements before and after anti-PD-L1 treatment in patients using multiplex immunoassay and proximity extension assays as a standardized assessment across studies may be considered to provide more consistent results [75][76][77] .…”