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

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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.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

The authors declare that no funds, grants, or other supports were received during the preparation of this manuscript.

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Author notes

  1. Jamila Talb and Paul Takam Kamga are contribute equally.

Authors and Affiliations

  1. Department of Pulmonary Diseases and Thoracic Oncology, APHP – Hopital Ambroise Paré, 9 Avenue Charles de Gaulle, 92100, Boulogne-Billancourt, France

    Jamila Talb, Adrien Costantini, Coraline Dumenil, Jennifer Dumoulin, Julia Ouaknine, Violaine Giraud & Etienne Giroux Leprieur

  2. Department of Pulmonology, Hopital Mignot, Versailles, France

    Jamila Talb, Cécile Dujon & Reza Azarian

  3. Université Paris-Saclay, UVSQ, EA 4340 BECCOH, Boulogne-Billancourt, France

    Paul Takam Kamga, Marie Mayenga, Adrien Costantini, Catherine Julié, Jean-François Emile & Etienne Giroux Leprieur

  4. Department of Pathology, APHP – Hopital Ambroise Paré, Boulogne-Billancourt, France

    Catherine Julié & Jean-François Emile

  5. Department of Pathology, Hopital André Mignot, Versailles, France

    Claire Glaser

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  1. Jamila Talb
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by JT, PTK and EGI. The first draft of the manuscript was written by JT and EGI, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Etienne Giroux Leprieur.

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Conflict of interest

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

Ethics approval

No ethics approval was needed for retrospective studies according to French legislation in force at the beginning of the study. Non-opposition form for retrospective data collection was provided to all patients. None objected to data collection.

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Informed consent was obtained from all individual participants included in the study.

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Talb, J., Takam Kamga, P., Mayenga, M. et al. Gene expression profile of high PD-L1 non-small cell lung cancers refractory to pembrolizumab. Cancer Immunol Immunother 71, 2791–2799 (2022). https://doi.org/10.1007/s00262-022-03206-4

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