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Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 12/2021

Open Access 01-12-2021 | Paraneoplastic Syndromes | Original Article

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

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

Published in: Cancer Immunology, Immunotherapy | Issue 12/2021

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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.
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Metadata
Title
Mechanistic insights into immune checkpoint inhibitor-related hypophysitis: a form of paraneoplastic syndrome
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
Publication date
01-12-2021
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 12/2021
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-021-02955-y

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