Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Aug:134:79-84.
doi: 10.1016/j.lungcan.2019.06.005. Epub 2019 Jun 5.

Heterogeneity of PD-L1 expression in non-small cell lung cancer: Implications for specimen sampling in predicting treatment response

Alexander Haragan  1 , John K Field  2 , Michael P A Davies  3 , Carles Escriu  4 , Aaron Gruver  5 , John R Gosney  6
Affiliations

Heterogeneity of PD-L1 expression in non-small cell lung cancer: Implications for specimen sampling in predicting treatment response

Alexander Haragan et al. Lung Cancer. 2019 Aug.

Abstract

Objectives: PD-L1 expression on tumour cells can guide the use of anti-PD-1/PD-L1 immune modulators to treat patients with non-small cell lung cancer (NSCLC). Heterogeneity of PD-L1 expression both within and between tumour sites is a well-documented phenomenon that compromises its predictive power. Our aim was to better characterise the pattern and extent of PD-L1 heterogeneity with a view to optimising tumour sampling and improve its accuracy as a biomarker.

Materials and methods: Expression of PD-L1 was assessed by immunochemistry using the SP263 clone in 107 resected primary NSCLCs and their nodal metastases. Intra-tumoural heterogeneity, defined as 'small-scale' (mm²), 'medium-scale' (cm²) and 'large-scale' (between tumour blocks), was assessed by digital imaging using a novel 'squares method'. Inter-tumoural heterogeneity between the primary tumours and their nodal metastases and between N1 and N2 nodal stages was also assessed.

Results: The majority of tumours demonstrated intra-tumoural heterogeneity (small-scale 78%, medium-scale 50%, large-scale 46%). Inter-tumoural heterogeneity between the primary and nodal metastases was present in 53% of cases and, in 17%, between N1 and N2 disease. These differences were occasionally sufficient to lead to discrepancy across the ≥1%, ≥25% and ≥50% cut-offs used to guide therapy.

Conclusion: Heterogeneity of PD-L1 expression is common, variable in scale and extent, and carries significant implications for its accuracy as a predictive biomarker. Extensive sampling reduces, but cannot eliminate, this inaccuracy.

Keywords: Heterogeneity; NSCLC; Nodal metastases; PD-L1; Programmed-death ligand-1.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Title: Intra-tumoural heterogeneity of PD-L1 as assessed by the ‘squares method’. Description: A section of primary NSCLC immunolabelled for PD-L1 (SP263) overlaid with non-overlapping, 1 cm² grids (outlined in red), each divided into 100 1 mm squares. The yellow inset highlights a group of 20 1 mm squares. Every 1 mm square was individually assessed for PD-L1 expression and constituted a different data point for examining heterogeneity. NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 2
Fig. 2
(a, b)Title: Intra-tumoural heterogeneity of PD-L1 expression; primary tumour. Description: Two sections of a primary NSCLC immunolabelled for PD-L1 (SP263). Fig. 2a demonstrates small scale heterogeneity. Fig. 2b demonstrates large scale heterogeneity. The red arrows highlight tumour cells strongly positive for PD-L1, the yellow arrows highlight tumour cells showing no expression. NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 3
Fig. 3
(a–d)Title: Inter-tumoural heterogeneity of PD-L1 expression. Description: Sections of a primary NSCLC and nodal metastases immunolabelled for PD-L1 (SP263). Fig. 3a demonstrates no expression (0% TPS) by the primary tumour, Fig. 3b demonstrates diffuse expression (100% TPS) in a nodal metastasis from the same patient as indicated by the red oval. Fig. 3c demonstrates minimal expression (<1% TPS) of PD-L1, as indicated by the red oval, in a metastasis in an N1 lymph node, Fig. 3d demonstrates expression by almost all of the cells (near 100% TPS) as exemplified by the zone in the red oval, in a metastasis in a different (N2) lymph node from the same patient. NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1; TPS, tumour proportion score. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Brahmer J., Reckamp K.L., Baas P. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N. Engl. J. Med. 2015;373(2):123–135. - PMC - PubMed
    1. Garon E.B., Rizvi N.A., Hui R. Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 2015;372(21):2018–2028. - PubMed
    1. Borghaei H., Paz-Ares L., Horn L. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 2015;373(17):1627–1639. - PMC - PubMed
    1. Fehrenbacher L., von Pawel J., Park K. Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer. J. Thorac. Oncol. 2018;13(8):1156–1170. - PubMed
    1. Herbst R.S., Baas P., Kim D.W. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–1550. - PubMed

Publication types

MeSH terms