Abstract
Circulating tumor cells (CTCs) hold great potential to answer key questions of how non-small cell lung cancer (NSCLC) evolves and develops resistance upon anti-PD-1/PD-L1 treatment. Currently, their clinical utility in NSCLC is compromised by a low detection rate with the established, Food and Drug Administration (FDA)-approved, EpCAM-based CellSearch® System. We tested an epitope-independent method (ParsortixTM system) and utilized it to assess PD-L1 expression of CTCs from NSCLC patients. We prospectively collected 127 samples, 97 of which were analyzed with the epitope-independent system in comparison to the CellSearch system. CTCs were determined by immunocytochemistry as intact, nucleated, CD45−, pankeratins (K)+ cells. PD-L1 status of CTCs was evaluated from 89 samples. With the epitope-independent system, ≥1 CTC per blood sample was detected in 59 samples (61%) compared to 31 samples (32%) with the EpCAM-based system. Upon PD-L1 staining, 47% of patients harbored only PD-L1+CTCs, 47% had PD-L1+ and PD-L1−CTCs, and only 7% displayed exclusively PD-L1−CTCs. The percentage of PD-L1+CTCs did not correlate with the percentage of PD-L1+ in biopsies determined by immunohistochemistry (p = 0.179). Upon disease progression, all patients showed an increase in PD-L1+CTCs, while no change or a decrease in PD-L1+CTCs was observed in responding patients (n = 11; p = 0.001). Our data show a considerable heterogeneity in the PD-L1 status of CTCs from NSCLC patients. An increase of PD-L1+CTCs holds potential to predict resistance to PD-1/PD-L1 inhibitors.
Highlights
Blockade of the interaction of programmed death ligand 1 (PD-L1) and its receptor PD-1 has revolutionized treatment of patients with non-small cell lung cancer (NSCLC) [1]
Parsortix system; matched cohort, sample included in the comparison between the CellSearch and the Parsortix system for circulating tumor cell (CTC) detection in non-small cell lung cancer (NSCLC)
Parsortix system; matched cohort, sample included in the comparison between the CellSearch and patients; programmed death ligand 1 (PD-L1) cohort, PD-L1 cohort, samples for which the PD-L1 status the Parsortix system for circulating tumor cell (CTC) detection in non-small cell lung cancer (NSCLC)
Summary
Blockade of the interaction of programmed death ligand 1 (PD-L1) and its receptor PD-1 has revolutionized treatment of patients with non-small cell lung cancer (NSCLC) [1]. Therapy with different anti-PD-1/PD-L1 antibodies was approved in NSCLC in the first- and second-line setting. A correlation between PD-L1 expression by tumor or immune cells and efficacy of anti-PD-1/PD-L1 antibodies has been confirmed in various trials. One possible explanation for these findings could be that a single tissue biopsy does not adequately reflect the heterogeneity of PD-L1 expression in stage IV NSCLC patients with multiple tumor sites. Dynamic changes of PD-L1 expression in tumor cells might occur before or under therapy with PD-1/PD-L1 inhibitors, leading to different sensitivity to PD-1/PD-L1 blockade which would be missed by one single biopsy
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