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

• Kanie, Keitaro

• Iguchi, Genzo

• Bando, Hironori

• Urai, Shin

• Shichi, Hiroki

• Fujita, Yasunori

• Matsumoto, Ryusaku

• Suda, Kentaro

• Yamamoto, Masaaki

• Fukuoka, Hidenori

• Ogawa, Wataru

• Takahashi, Yutaka

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.

Journal

• Cancer Immunology, Immunotherapy

  Cancer Immunology, Immunotherapy 70 (12), 3669-3677, 2021-12

  Springer

Keywords

• Autoimmunity
• Immune checkpoint inhibitor
• Hypopituitarism
• Hypophysitis
• Paraneoplastic syndrome

Details

• CRID: 1050575520344997760
• NII Article ID: 120007168987
• NII Book ID: AA00598499
• DOI: 10.1007/s00262-021-02955-y
• ISSN: 14320851
• ISSN: 03407004
• HANDLE: 20.500.14094/90008773
• Web Site: https://link.springer.com/content/pdf/10.1007/s00262-021-02955-y.pdf
• Web Site: https://link.springer.com/article/10.1007/s00262-021-02955-y/fulltext.html
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN