Impact of Kras mutant subtypes on PD-L1 expression in lung adenocarcinoma

Date

10 Oct 2016

Session

Poster display

Presenters

Alexander Falk

Citation

Annals of Oncology (2016) 27 (6): 15-42. 10.1093/annonc/mdw363

Authors

A.T. Falk1, N. Yazbeck1, L. Thon1, N. Guibert2, V. Hofman3, K. Zahaf3, V. Lespinet3, O. Bordone4, V. Tanga4, K. Washetine4, C. Cohen5, N. Venissac5, J. Mouroux5, C. Marquette6, P. Brest1, M. Ilié7, P. Hofman7

Author affiliations

  • 1 Inserm U1081/umr Cnrs 7284, Team 3, Institue for Research on Cancer and Ageing, 06000 - Nice/FR
  • 2 Thoracic Oncology, CHU Toulouse, Hôpital de Larrey, Toulouse/FR
  • 3 Laboratory Of Clinical And Experimental Pathology / Liquid Biopsy Laboratory, Pasteur Hospital, Nice/FR
  • 4 Hospital-integrated Biobank (bb-0033-00025), Pasteur Hospital, Nice/FR
  • 5 Department Of Thoracic Surgery, Pasteur Hospital, Nice/FR
  • 6 Department Of Pneumology, Pasteur Hospital, Nice/FR
  • 7 Inserm U1081/umr Cnrs 7284, Team 3, Institute for Research on Cancer and Ageing, 06000 - Nice/FR
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Background

Clinical responses to immune checkpoint blockade by anti-PD-1/PD-L1 monoclonal antibodies in non-small-cell lung cancer (NSCLC) may be associated with PD-L1 expression. This study was undertaken to determine the expression profile of PD-L1 in patients with Kras-mutant lung adenocarcinoma (LUAD) and to investigate the activation of Kras codon subtypes as a mechanism of PD-L1 regulation.

Methods

PD-L1 expression was evaluated by IHC (SP142 clone, Ventana) on 117 LUAD (KrasWT, n = 51; Krasmut, n = 66). Stable cell lines were generated by transfection of Kras-G12D, G12V, G12C and WT plasmids into Beas2B bronchial cells.

Results

IHC analysis showed higher expression of PD-L1 in both tumor and immune cells in Kras-mutant LUAD compared with KrasWT tumors (37% vs. 18%; P = 0.005). Kras-mutant PD-L1+ tumors had increased CD66b+ neutrophil infiltrates and lower CD8+ T-cell content than PD-L1 tumors. In vitro, mutant Kras led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, notably in KrasG12C and KrasG12V cells, suggesting PD-L1 transcriptional regulation. There was differential activation of NF-kB, ERK and Pi3k/Akt pathways between Kras-mutant subtypes. In addition, PD-L1 was upregulated 3-fold by stimulation with IFNɣ, independently of the Kras codon subtypes. Instead, hypoxia significantly increased PD-L1 expression in KrasG12C and KrasG12D cells. Co-culture experiments with human PBMCs from healthy patients were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 expression by tumor cells induced by Kras mutations led to decreased PBMCs proliferation and increased apoptosis. An anti-PD-L1 checkpoint inhibitor is currently being tested as single agent or in combination with ERK or PI3K inhibitors in our Kras cell models.

Conclusions

PD-L1 is expressed in 37% of Kras mutant LUAD, suggesting PD-L1 as a therapeutic target in this subset. According to the Kras mutation subtype, potential drugs targeting the NF-kB, ERK or Pi3k/Akt pathways may additionally increase the antitumor adaptive immune responses.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

Pasteur Hospital, Nice

Disclosure

All authors have declared no conflicts of interest.

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