Abstract
Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients. PD-L1 tumor expression, along with tumor mutational burden, is currently being explored as a predictive biomarker for responses to immune checkpoint inhibitors (ICIs). However, lung cancer patients may have insufficient tumor tissue samples and the high bleeding risk often prevents additional biopsies and, as a consequence, immunohistological evaluation of PD-L1 expression. In addition, PD-L1 shows a dynamic expression profile and can be influenced by intratumoral heterogeneity as well as the immune cell infiltrate in the tumor and its microenvironment, influencing the response rate to PD-1/PD-L1 axis ICIs. Therefore, to identify subgroups of patients with advanced NSCLC that will most likely benefit from ICI therapies, molecular characterization of PD-L1 expression in circulating tumor cells (CTCs) might be supportive. In this review, we highlight the use of CTCs as a complementary diagnostic tool for PD-L1 expression analysis in advanced NSCLC patients. In addition, we examine technical issues of PD-L1 measurement in tissue as well as in CTCs.
Highlights
Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients
Immune checkpoint inhibition therapy represents a breakthrough in treatment of non-small cell lung cancer patients
There are still major challenges in selecting NSCLC patients likely to benefit from targeting the PD-1/PD-L1 axis
Summary
Despite the reported value of assessing the overexpression of PD-L1 on cells of different types in solid tumors—including lung cancer—as a promising marker to predict anti PD-1/PD-L1 treatment efficacy, the predictive value of PD-L1 expression is still controversial and related investigations face the three major limitations of tissue biopsies: Invasiveness, sampling error due to tumor heterogeneity, and mostly unfeasible longitudinal sampling. Tumor-infiltrating lymphocytes (TILs) were significantly associated with prolonged disease-free survival of these patients, whereas PD-L1 and PD-L2 expression had no significant prognostic implications He and colleagues [36] revealed a 43.2% positive PD-1 staining on TILs in NSCLC tumor tissue, while PD-L1 was detected on both tumor cells and TILs. Studies investigating the relation between. One of the major issues in translating PD-L1+ (circulating) tumor cells from basic research to the clinical setting for routine diagnostic application is (i) a heterogeneous detection rate of used CTC enrichment and detection approaches, (ii) resulting observer bias in calling CTCs, and (iii) the lack of consensus on the use of different commercially available anti-PD-L1 antibody clones and their performance and specificity compared to the antibody clones that are included in the IHC kits that received regulatory approval
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