Sensitive detection of PD-L1 expression on circulating epithelial tumor cells (CETCs) could be a potential biomarker to select patients for treatment with PD-1/PD-L1 inhibitors in early and metastatic solid tumors

Abstract

BackgroundThe current cancer research strongly focuses on immune therapies, where the PD-1, with its ligands plays an important role. It is known that PD-L1 is frequently up-regulated in a number of different cancers and the relevance of this pathway has been extensively studied and therapeutic approaches targeting PD-1 and PD-L1 have been developed. We used a non-invasive, real-time biopsy for determining PD-L1 and PD-L2 expression in CETCs of solid cancer patients.MethodsCETCs were determined from blood of 128 patients suffering from breast (72), prostate (27), colorectal (18) and lung (11) cancer. The number of vital CETCs and the expression of PD-L1 and PD-L2 were investigated using the maintrac® method.ResultsPD-L1 expressing CETCs were detected in 94.5% of breast, 100% of prostate, 95.4% of colorectal and 82% of lung cancer patients whereas only 75% of breast cancer patients had PD-L2 positive CETCs. In the PD-L1 and PD-L2 expressing patients the cell fraction of PD-L1 positive CETCs is significantly higher than the fraction of PD-L2 positive CETCs (54.6% vs. 28.7%; p<0.001). Breast cancer patients with metastatic disease had significantly more PD-L1 positive CETCs as compared to patients without metastasis (median 75% vs. 61.1%; p<0.05).ConclusionPD-L1 seems to be a major factor in immune evasion and is highly expressed on CETCs regardless of the type of cancer. Monitoring the frequency of PD-L1 positive CETCs could reflect individual patient's response for an anti-PD-1/PD-L1 therapy and may be a promising target of anticancer treatment.

Molecular profiling for precision cancer therapies

“…Potential clinical uses of blood-based CTC and ctDNA that are not offered by tumor tissue sequencing include monitoring the persistence of radiologically undetectable tumors (e.g., minimal or molecular residual disease), prediction of recurrence (e.g., persistent CTC associated with risk of relapse in breast cancer) [60], monitoring of treatment response (e.g., CTC dynamics in prostate and breast cancer patients treated with chemotherapy) [61,62], early detection of resistance mechanisms [63,64], assessment of tumor burden (e.g., correlation between tumor burden and ctDNA variant allele frequency in NSCLC) [65], tracking the clonal evolution of tumors [66], and dynamic evaluation of immune biomarkers such as PD-L1 expression and tumor mutation burden [67][68][69].…”

Liquid biopsy in the era of immuno-oncology: is it ready for prime-time use for cancer patients?

“…The evaluation of PD-L1 expression on CTCs has been assessed in different solid tumors including lung [66,[78][79][80][81][82][83][84], bladder [85], breast [86], HNSCC [87,88], colon [84,89] and prostatic carcinoma [84,89] (Table 2). Independently of the technical issues cited above, other challenges rapidly emerged: (i) is PD-L1 expressed on all CTCs or only in a subpopulation of CTCs?…”

Immuno-Oncology Biomarkers for Personalized Immunotherapy in Breast Cancer

“…The first study on expression of PD-L1 on CTCs was reported in patients with metastatic breast carcinoma (Mazel et al, 2015), and later it was investigated in other types of cancer. Further study on CTC/PD-L1 indicated that the frequency of PD-L1 positive CTCs are significantly higher in metastatic breast cancer patients compared to non-metastatic patients (Schott et al, 2017). These findings suggested CTC/PD-L1 assay as a potential non-invasive marker for stratification of patients benefiting from anti-PD-L1 therapies in clinical trials (Mazel et al, 2015;Schott et al, 2017).…”

“…Further study on CTC/PD-L1 indicated that the frequency of PD-L1 positive CTCs are significantly higher in metastatic breast cancer patients compared to non-metastatic patients (Schott et al, 2017). These findings suggested CTC/PD-L1 assay as a potential non-invasive marker for stratification of patients benefiting from anti-PD-L1 therapies in clinical trials (Mazel et al, 2015;Schott et al, 2017). The expression of another important immune checkpoint member, B7-H3, on CTCs of breast cancer patients has been also reported.…”