RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies

Rena Pollack*, Joshua Stokar, Natan Lishinsky, Irina Gurt, Naomi Kaisar-Iluz, Merav E. Shaul, Zvi G. Fridlender, Rivka Dresner-Pollak

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Immune checkpoint inhibitors (ICI) are commonly associated with thyroid immune-related adverse events, yet the mechanism has not been fully elucidated. We aimed to further explore the mechanism of ICI-induced thyroid dysfunction by assessing changes induced in the thyroid transcriptome by ICI treatment (αPD-1/αPD-L1) in a lung cancer murine model. RNA-sequencing of thyroid tissues revealed 952 differentially expressed genes (DEGs) with αPD-1 treatment (|fold-change| ≥1.8, FDR < 0.05). Only 35 DEG were identified with αPD-L1, and we therefore focused on the αPD-1 group alone. Ingenuity Pathway Analysis revealed that of 952 DEGs with αPD-1 treatment, 362 were associated with functions of cell death and survival, with predicated activation of pathways for apoptosis and necrosis (Z = 2.89 and Z = 3.21, respectively) and negative activation of pathways for cell viability and cell survival (Z = −6.22 and Z = −6.45, respectively). Compared to previously published datasets of interleukin-1β and interferon γ-treated human thyroid cells, apoptosis pathways were similarly activated. However, unique changes related to organ inflammation and upstream regulation by cytokines were observed. Our data suggest that there are unique changes in gene expression in the thyroid associated with αPD-1 therapy. ICI-induced thyroid dysfunction may be mediated by increased tissue apoptosis resulting in destructive thyroiditis.

Original languageAmerican English
Article number10526
JournalInternational Journal of Molecular Sciences
Volume24
Issue number13
DOIs
StatePublished - 23 Jun 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • anti PD-1
  • immune checkpoint inhibitors
  • immune related adverse events
  • thyroid
  • transcriptome

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