Immune marker profiling and PD-L1/PD-L2 expression mechanisms of Tumor Infiltrating Lymphocytes across NSCLC mutations

Immune checkpoint inhibitors of the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) are of significant clinical value for the treatment of non-small cell lung cancer (NSCLC), particularly in patients expressing PD-L1. However, their full clinical efficacy in NSCLC patients exhibiting different mutations, namely KRAS and Epidermal Growth Factor Receptor (EGFR) activating mutations, remains unclear. A recent abstract on a study conducted by Toki et al. (Yale School of Medicine, US) presented at the 2017 ASCO conference provides a scientific rationale on why EFGR mutants are not immune reactive and respond poorly to immune-oncology (IO) therapies. The authors investigated PD-L1 versus PD-L2 expression, and characterised tumour infiltrating lymphocytes (TILs) and their activation status as a function of the known mutation profile in over 150 NSCLC patient tumours, using AQUA-based quantitative fluorescence (QIF). The proximity ligation assay (PLA) was specifically used to measure active in situ EGFR signalling. 

Results show that EGFR mutant tumours exhibited significantly lower PD-L1 tumour and stroma expression, and higher PD-L2, compared to KRAS mutant and wild-type (WT) tumours. Interestingly, findings indicate a very high frequency of inactive TILs in patient EGFR mutant tumours despite the presence of lymphocytes in the tumour microenvironment, in contrast to KRAS mutants, possibly explaining the low immune therapy response rates seen in these patients. Moreover, PLA-defined activated EGFR was found to correlate with increased PD-L1 expression in EGFR mutants, but not in their WT counterpart, while TIL activation was associated with higher PD-L1 in WT tumours. Interestingly, according to Toki et al. these findings suggest that PD-L1 expression may fail to predict responses because of constitutive oncogenic signalling, rather than immune-mediated signalling.

Rudy Hovelinck
Diagnostics Manager AstraZeneca

NS ID BE-1565-RD05/2018-LB Local code 509

Rudy Hovelinck obtained a scientific degree first in biochemistry at Ghent University and later in Molecular Biology at the ULB. Initially exploring the academic world in diverse fields as genetics, protein chemistry and virology, he soon realised that bridging scientific knowledge to the medical world was a more meaningful way of spending his professional life. This journey started in the field of pathology biomarker testing, introducing HER2 IHC and ISH testing for patient therapy selection and continued in the field of molecular oncology. Today at AstraZeneca he works as a diagnostics manager. In this role he is passionately contributing to the successful introduction of novel biomarkers and support current testing strategies for patient selection. In his own time he enjoys travelling with his family exploring the world and spending time close to nature. Specialties: Oncology, Anatomic Pathology, Biomarker Development, Medical Devices.