Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome.
Adrenal Insufficiency
/ immunology
Adult
Aged
Aged, 80 and over
Animals
B7-H1 Antigen
/ immunology
CTLA-4 Antigen
/ immunology
Corticotrophs
/ immunology
Female
Humans
Hypophysitis
/ immunology
Immune Checkpoint Inhibitors
/ therapeutic use
Immunotherapy
/ methods
Male
Mice
Middle Aged
Neoplasms
/ immunology
Paraneoplastic Syndromes
/ immunology
Pro-Opiomelanocortin
/ immunology
Programmed Cell Death 1 Receptor
/ immunology
Retrospective Studies
Autoimmunity
Hypophysitis
Hypopituitarism
Immune checkpoint inhibitor
Paraneoplastic syndrome
Journal
Cancer immunology, immunotherapy : CII
ISSN: 1432-0851
Titre abrégé: Cancer Immunol Immunother
Pays: Germany
ID NLM: 8605732
Informations de publication
Date de publication:
Dec 2021
Dec 2021
Historique:
received:
13
11
2020
accepted:
28
04
2021
pubmed:
13
5
2021
medline:
18
11
2021
entrez:
12
5
2021
Statut:
ppublish
Résumé
Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens. Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined. Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not. We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.
Sections du résumé
BACKGROUND
BACKGROUND
Immune checkpoint inhibitors (ICIs) as a cancer immunotherapy have emerged as a treatment for multiple advanced cancer types. Because of enhanced immune responses, immune-related adverse events (irAEs), including endocrinopathies such as hypophysitis, have been associated with the use of ICIs. Most underlying mechanisms of ICI-related hypophysitis remain unclear, especially for programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) inhibitors. We hypothesized that ICI-related hypophysitis is associated with paraneoplastic syndrome caused by ectopic expression of pituitary-specific antigens.
METHODS
METHODS
Twenty consecutive patients with ICI-related hypophysitis between 2017 and 2019 at Kobe University Hospital were retrospectively analyzed. Circulating anti-pituitary antibodies were detected using immunofluorescence staining and immunoblotting. Ectopic expression of pituitary autoantigens in tumor specimens was also examined.
RESULTS
RESULTS
Eighteen patients were treated with PD-1/PD-L1 inhibitors, and two were treated with a combination of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 inhibitors. All patients showed adrenocorticotropic hormone (ACTH) deficiency and additionally, three showed thyroid-stimulating hormone (TSH) deficiency, and one showed gonadotropin-releasing hormone (GnRH) deficiency. Among these patients, three exhibited anti-pituitary antibodies, two with anti-corticotroph antibody and one with anti-somatotroph antibody. Interestingly, the anti-corticotroph antibody recognized proopiomelanocortin (POMC) and those two patients exhibited ectopic ACTH expression in the tumor, while the patients without anti-corticotroph antibody did not.
CONCLUSIONS
CONCLUSIONS
We demonstrated 10% of PD-1/PD-L1 inhibitors-related hypophysitis were associated with the autoimmunity against corticotrophs and maybe caused as a form of paraneoplastic syndrome, in which ectopic expression of ACTH in the tumor was observed. It is also suggested that the pathophysiology is heterogenous in ICI-related hypophysitis.
Identifiants
pubmed: 33977343
doi: 10.1007/s00262-021-02955-y
pii: 10.1007/s00262-021-02955-y
pmc: PMC8571153
doi:
Substances chimiques
B7-H1 Antigen
0
CTLA-4 Antigen
0
Immune Checkpoint Inhibitors
0
Programmed Cell Death 1 Receptor
0
Pro-Opiomelanocortin
66796-54-1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3669-3677Subventions
Organisme : the Japan Society for the Promotion of Science
ID : 23659477 and 26670459
Organisme : the Japan Society for the Promotion of Science
ID : 15K09431 and 18K08514
Organisme : Japan Agency for Medical Research and Development
ID : 17bm0804012h0001
Organisme : the Japan Society for the Promotion of Science
ID : 17K16165
Informations de copyright
© 2021. The Author(s).
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