Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome.

Abstract

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:

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:

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:

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.

• Authors: Keitaro Kanie, Genzo Iguchi, Hironori Bando, Shin Urai, Hiroki Shichi, Yasunori Fujita, Ryusaku Matsumoto, Kentaro Suda, Masaaki Yamamoto, Hidenori Fukuoka, Wataru Ogawa, Yutaka Takahashi
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 70 Issue 12 Pg. 3669-3677 (Dec 2021) ISSN: 1432-0851 [Electronic] Germany
• PMID: 33977343 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• B7-H1 Antigen
• CTLA-4 Antigen
• Immune Checkpoint Inhibitors
• Programmed Cell Death 1 Receptor
• Pro-Opiomelanocortin

Topics

• Adrenal Insufficiency (immunology, therapy)
• Adult
• Aged
• Aged, 80 and over
• Animals
• B7-H1 Antigen (immunology)
• CTLA-4 Antigen (immunology)
• Corticotrophs (immunology)
• Female
• Humans
• Hypophysitis (immunology, therapy)
• Immune Checkpoint Inhibitors (therapeutic use)
• Immunotherapy (methods)
• Male
• Mice
• Middle Aged
• Neoplasms (immunology, therapy)
• Paraneoplastic Syndromes (immunology, therapy)
• Pro-Opiomelanocortin (immunology)
• Programmed Cell Death 1 Receptor (immunology)
• Retrospective Studies