Correlation between PD-1 and PD-L1 expression profile, NLR, LDH and Objective Response Rate, PFS and OS in advanced NSCLC after immunotherapy

The PD-L1 expression in cancer cells is dynamic and mutable because it is a patho-physiologically inducible factor and it will be a continuous variable starting from zero through low to high levels. Anti-PD-L1 immunohistochemistry may not represent the actual status of the tumour because of individual variability, tumour heterogeneity and biology. Additionally, as aforementioned, there may be analytical variability due to the use of different assays and antibodies to detect PD-L1. Every different test uses specific and unique IHC detection antibodies for PD-L1 staining 32, 49, 54, 72-75, 79-81. As a result, we don’t know how these company-made tests perform when compared with each other, it could be predictable that all these assays will stain cancer cells differently, contributing to increase the unreliability in defining PD-L1 expression status. For instance, one study described significant inter-assay variability or discordance when assessing PD-L1 expression using two different detection antibodies (SP142 and E1L3N) 82.
Furthermore, every IHC detection antibody and therapeutic antibodies engage PD-L1 at different sites 83.
The performance of PD-L1 assays is also influenced by cut-offs levels for positivity because very low thresholds may fail to increase the differences in response between positive and negative groups.
To summarize, the lack of uniform and standardized approaches to assessing PD-L1 expression with IHC and the absence of a clear consensus about thresholds above which a positive PD-L1 expression is defined, leads to difficulties in comparing data across clinical trials.
Also, biological issues could limit the use of PD-L1 IHC. Several studies showed that PD-L1 expression is also regulated by oncogenic drivers in NSCLC, such as EGFR, echinoderm microtubule-associated protein like 4 (EML4–ALK), proto-oncogene tyrosine-protein kinase ROS (ROS1), KRAS, tumour protein p53 (TP53), mesenchymal-to-epithelial transition (MET) and phoasphatidylinositol-4,5 bisphosphate 2-kinase catalytic subunit alpha (PIK3CA)112. Several studies showed that EGFR pathway activation was associated with higher PD-L1 expression 113-116. It has been shown that EGFR-mutant NSCLC cell lines compared to EGFR wild-type (WT) cell lines have a significantly higher protein expression of PD-L1. EGFR activated by EGF stimulation, exon-19 deletion and L858R mutation induced PD-L1 expression, suggesting that constitutive oncogene pathway activation can up-regulate PD-L1. Hong et al. found that overexpression of ALK fusion protein increased PD-L1 expression through p-ERK1/2 and p-AKT signalling in NSCLC cells 117. Therefore, EML4–ALK fusion protein represents intrinsic regulation of PD-L1 in NSCLC with EML4–ALK gene fusion. They demonstrated that up-regulation of PD-L1 by EML4–ALK fusion protein induced the apoptosis of T-cells through the PD-L1–PD-1 axis. Inhibiting ALK by sensitive TKIs can reverse the suppression of T-cells and reduce PD-L1 expression. [...]