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
. 2022 Nov;71(11):2791-2799.
doi: 10.1007/s00262-022-03206-4. Epub 2022 Apr 18.

Gene expression profile of high PD-L1 non-small cell lung cancers refractory to pembrolizumab

Jamila Talb  1   2 , Paul Takam Kamga  3 , Marie Mayenga  3 , Adrien Costantini  1   3 , Catherine Julié  3   4 , Coraline Dumenil  1 , Jennifer Dumoulin  1 , Julia Ouaknine  1 , Violaine Giraud  1 , Cécile Dujon  2 , Reza Azarian  2 , Claire Glaser  5 , Jean-François Emile  3   4 , Etienne Giroux Leprieur  6   7
Affiliations

Gene expression profile of high PD-L1 non-small cell lung cancers refractory to pembrolizumab

Jamila Talb et al. Cancer Immunol Immunother. 2022 Nov.

Abstract

Background: Despite high expression of PD-L1, around half of advanced non-small cell lung cancer (NSCLC) will not experience tumor response with pembrolizumab. There is an need for a better understanding of the resistance mechanisms in this setting.

Methods: This bi-centric retrospective study included all consecutive patients with PDL1 ≥ 50% advanced NSCLC treated with pembrolizumab in first-line treatment between 2016 and 2020. We compared the clinical characteristics of patients with early progression (refractory) vs others. We performed a comprehensive gene expression profile screening by RNAseq capture on tumor samples.

Results: We included 46 patients. Twenty-two patients were refractory to pembrolizumab, mainly women, with poor performance status and lower albumin concentration. RNAseq analysis was performed on 19 samples. Hierarchical clustering allowed the identification of 3 clusters with various proportion of refractory tumors: intermediate (C1: 57%), high (C2: 71%) and low proportion (C3: 40%). Comparative analysis between C2 and C3 allowed the identification of overexpressed (n = 137) and underexpressed (n = 40) genes. Among the genes of interest, C2 exhibits higher activation of pathways associated with stemness phenotype (Hedgehog, Notch and Hippo pathways) and pathways associated with loss of PTEN and JAK2. In C2, genes associated with PD-1, toll-like receptor-9 (TLR-9), major histocompatibility complex (MHC) and interferon-γ pathways were underexpressed.

Conclusion: This study gives an overview of activated and downregulated pathways in high PD-L1 NSCLC refractory to pembrolizumab. These tumors showed activation of pathways associated with cancer stem cells, loss of PTEN and JAK2, and inhibition of both priming and effector phases of the immune response.

Keywords: Non-small cell lung cancer; PD-L1; Pembrolizumab; RNAseq; Resistance.

PubMed Disclaimer

Conflict of interest statement

EGL: MSD (advisory board). Other authors declare no potential conflicts of interest.

Figures

Fig. 1
Fig. 1
Hierarchical clustering according to RNAseq analysis (n = 19)
Fig. 2
Fig. 2
Differential analysis of gene expression between C2 and C3 clusters
Fig. 3
Fig. 3
Overexpressed genes of interest in C2 compared to C3 using GSEA enrichment analysis. a stemness maintenance-associated pathways; b Hedgehog signaling pathway; c Notch signaling pathway; d Hippo signaling pathway; e pathways associated with loss of PTEN; f pathways associated with loss of JAK2
Fig. 4
Fig. 4
Underexpressed genes of interest in C2 compared to C3 using GSEA enrichment analysis. a MHC-associated pathway; b pathways associated with response to IFN-γ; c PD-1-associated pathway; d toll-like receptor-9-associated pathway
See this image and copyright information in PMC

References

    1. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–1833. doi: 10.1056/NEJMoa1606774. - DOI - PubMed
    1. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, Chaput N, Eggermont A, Marabelle A, Soria JC, Ferté C. Hyperprogressive disease is a new pattern of progression in cancer patients treated by Anti-PD-1/PD-L1. Clin Cancer Res. 2014;23(8):1920–1928. doi: 10.1158/1078-0432.CCR-16-1741. - DOI - PubMed
    1. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078–2092. doi: 10.1056/NEJMoa1801005. - DOI - PubMed
    1. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040–2051. doi: 10.1056/NEJMoa1810865. - DOI - PubMed
    1. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–284. doi: 10.1038/nrc1590. - DOI - PubMed

MeSH terms

LinkOut - more resources