PD-L1 Expression by Two Complementary Diagnostic Assays and mRNA In Situ Hybridization in Small Cell Lung Cancer

Abstract

Introduction Therapeutic antibodies to immune checkpoints show promising results. Programmed death-ligand 1 (PD-L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD-L1 receptor (programmed death 1). We investigated PD-L1 protein expression and messenger RNA (mRNA) levels in SCLC. Methods PD-L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28-8 PD-L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor-infiltrating immune cells (TIICs) obtained from a limited-disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive-disease SCLC was assessed for PD-L1 protein expression in tumor cells with Dako 28-8 antibody only. Results The overall prevalence of PD-L1 protein expression in tumor cells was 16.5%. In the limited-disease cohort, the prevalences of PD-L1 protein expression in tumor cells with SP142 and Dako 28-8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD-L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD-L1 protein/mRNA expression was associated with the presence of more TIICs (p < 0.05). The extensive-disease cohort demonstrated a 14.9% positivity of PD-L1 protein expression in tumor cells with Dako 28-8 antibody. Conclusions A subset of SCLCs is characterized by positive PD-L1 and/or mRNA expression in tumor cells. Higher PD-L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD-L1 in SCLC is lower than that published for NSCLC. The predictive role of PD-L1 expression in SCLC treatment remains to be established.

A reliable and feasible way to predict the benefits of Nivolumab in patients with non-small cell lung cancer: a pooled analysis of 14 retrospective studies

“…As shown in Figure 2B, the pooled HRs of OS from eight studies 16,18,19,28,30,33,35,36 using random effect model was 1.75(95%CI: 1.33, 2.30), favoring NSCLC patients with low pre-treatment NLR.

10.1080/2162402X.2018.1507262-F0002Figure 2.Comparisons of PFS and OS in Nivolumab treated NSCLC patients with different baseline NLR. A, NLR < cutoff value(low NLR) versus NLR≥ cutoff value(high NLR) for PFS; B, NLR < cutoff value versus NLR≥ cutoff value for OS.

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“…After removing duplication and reviewing titles and abstracts, 126 of them were discarded and the left 18 studies were included for more detailed selection. Finally, 130 of the initial studies were excluded and the left 14 retrospective studies 16–19,26–35 were considered as eligible for the combined analysis after reviewing the full text. We also planned to assess the role of NLR in predicting anti-PD-1/PD-L1 agents, including Pembrolizumab, Atezolizumab, and Durvalumab.…”

“…We extracted data of PFS and OS from individual studies 16–19,26–35 . As shown in Supplemental Table 1, the median OS ranged from 6.5 to 17 months, while the median PFS was between 2.1 and 5.5 months.…”

“…By combining HRs of high NLR versus low NLR with regard to PFS from 10 studies, 16–19,26,28,32,33,35,36 the pooled result using random effect model showed that the estimated effect was 1.44(95%CI: 1.18, 1.77), indicating NSCLC patients with low pre-treatment NLR had a 1.44 times of getting better PFS(Figure 2A). As shown in Figure 2B, the pooled HRs of OS from eight studies 16,18,19,28,30,33,35,36 using random effect model was 1.75(95%CI: 1.33, 2.30), favoring NSCLC patients with low pre-treatment NLR.

10.1080/2162402X.2018.1507262-F0002Figure 2.Comparisons of PFS and OS in Nivolumab treated NSCLC patients with different baseline NLR.

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“…As there were several studies 16,18,19,28,33,35 set the cutoff value of pre-treatment NLR being 5, we used the value of 5 to find out the influence of different cutoff value on PFS and OS. The studies 16-19,26,28,32,33,35,36 included reported the HRs of high NLR versus low NLR on PFS in the treatment of advanced NSCLC.…”