RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies
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 treatm...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/13/10526 |
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| author | Rena Pollack Joshua Stokar Natan Lishinsky Irina Gurt Naomi Kaisar-Iluz Merav E. Shaul Zvi G. Fridlender Rivka Dresner-Pollak |
| author_facet | Rena Pollack Joshua Stokar Natan Lishinsky Irina Gurt Naomi Kaisar-Iluz Merav E. Shaul Zvi G. Fridlender Rivka Dresner-Pollak |
| author_sort | Rena Pollack |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T01:39:50Z |
| format | Article |
| id | doaj.art-33df538aed2848ddaf90600da45def79 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T01:39:50Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-33df538aed2848ddaf90600da45def792023-11-18T16:39:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-06-0124131052610.3390/ijms241310526RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 AntibodiesRena Pollack0Joshua Stokar1Natan Lishinsky2Irina Gurt3Naomi Kaisar-Iluz4Merav E. Shaul5Zvi G. Fridlender6Rivka Dresner-Pollak7Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 91120, IsraelDepartment of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 91120, IsraelDepartment of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 91120, IsraelDepartment of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 91120, IsraelFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelFaculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, IsraelDepartment of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem 91120, IsraelImmune 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.https://www.mdpi.com/1422-0067/24/13/10526immune checkpoint inhibitorsanti PD-1thyroidimmune related adverse eventstranscriptome |
| spellingShingle | Rena Pollack Joshua Stokar Natan Lishinsky Irina Gurt Naomi Kaisar-Iluz Merav E. Shaul Zvi G. Fridlender Rivka Dresner-Pollak RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies International Journal of Molecular Sciences immune checkpoint inhibitors anti PD-1 thyroid immune related adverse events transcriptome |
| title | RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies |
| title_full | RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies |
| title_fullStr | RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies |
| title_full_unstemmed | RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies |
| title_short | RNA Sequencing Reveals Unique Transcriptomic Signatures of the Thyroid in a Murine Lung Cancer Model Treated with PD-1 and PD-L1 Antibodies |
| title_sort | rna sequencing reveals unique transcriptomic signatures of the thyroid in a murine lung cancer model treated with pd 1 and pd l1 antibodies |
| topic | immune checkpoint inhibitors anti PD-1 thyroid immune related adverse events transcriptome |
| url | https://www.mdpi.com/1422-0067/24/13/10526 |
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