Most cancer deaths are associated with metastasis, where little, if any, therapeutic options are available.
Immune checkpoint regulators such as PD-L1 have become exciting new therapeutic targets leading to long lasting remissions in patients with advanced and metastatic cancers. However, in view of the costs and the toxicity profiles therapies, robust predictive biomarkers are urgently needed. Indeed, the grading of PD-L1 expression by histological assessment on invasive tumor biopsy may not reflect overall tumor biology and heterogeneity (Ilié, 2016a/ b; Hofman, 2017).
Towards establishing circulating tumor cells (CTC) as potential screening biomarkers, i/ we first developed a protocol to isolate specifically CTC (Hofman 2011a/ b) and to immunostain for PD-L1 (ISET® platform, partnership with Genentech); ii/ we successfully reported the overexpression of PD-L1 on metastatic cells circulating in the blood of some, but not all patients with advanced lung cancer (NSCLC); iii/ we correlated the PD-L1 expression in CTCs and matched lung biopsies, providing CTCs assessment as potential predictive biomarker; iv/ we demonstrated through this proof-of-concept study the potential of CTC/PD-L1 assay as a noninvasive real-time liquid biopsy for patient stratification and potential predictive biomarker (Ilié M. 2018).
Despite its promising predictive therapeutic value, the use of PD-L1 score is limited by high rates of 'false positive' or 'false negative' patients (Reck M, 2016; Robert, 2015a; Ribas, 2016), due to the heterogeneous expression of PD-L1 (Ilie, 2016). Moreover, the expression of the immune checkpoint proteins is highly dynamic and influenced by the microenvironment. Thus, the static picture of a PD-L1 staining in biopsy and/or in CTCs may not accurately predict therapy efficiency in all NSCLC patients.
Our project will now take complementary approaches (molecular and cellular biology, dynamic single-cell approaches, in vivo and ex vivo strategies) to define signaling pathways regulating PD-L1 expression and to characterize within coexpression signatures, long lived biomarkers that could provide a PD-L1 attractive alternative companion test for anti-PD1/PD-L1 immunotherapies.
