A Common Pituitary Autoantibody in Two Patients with Immune Checkpoint Inhibitor-Mediated Hypophysitis: ZCCHC8

Abstract

<jats:sec><jats:title>Objective:</jats:title><jats:p> Hypophysitis is an increasingly recognized adverse effect of immune checkpoint inhibitor (ICI) therapy for malignancy. However, the mechanisms through which ICIs induce hypophysitis are largely unknown. We aim to describe 2 cases of ICI-mediated hypophysitis and perform autoantibody profiling on serial samples from these patients to determine if common autoantibodies could be identified. </jats:p></jats:sec><jats:sec><jats:title>Methods:</jats:title><jats:p> We describe 2 cases of patients with metastatic urothelial cancer who received ICI therapy and subsequently developed severe fatigue, prompting a hormonal workup consistent with hypopituitarism. Patient 1 received the ICI ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) and patient 2 received the ICI pembrolizumab (anti-programmed cell death protein 1). Both patients had serial seromic immune biomarker profiling using high-density protein arrays before and after developing hypophysitis. Once a common autoantibody was found, zinc finger CCHC-type containing 8 (ZCCHC8), we used immunohistochemistry to assess its presence in pituitary tissue. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Of a limited number of increased autoantibodies detected, those to ZCCHC8 were the only common antibodies to increase at least 3-fold post-hypophysitis in both patients. Using immunohistochemistry staining, we show for the first time that ZCCHC8 is expressed in pituitary gland tissue. </jats:p></jats:sec><jats:sec><jats:title>Conclusion:</jats:title><jats:p> Seromic profiling identified a common autoantibody, ZCCHC8, in 2 patients who developed hypophysitis on ICI therapy, and other serial autoantibody increases in each patient. These findings warrant validation in other cohorts to determine if the response is to self or tumor antigen, and may reveal novel insights into pituitary gland physiology and the pathogenesis of ICI-mediated hypophysitis. </jats:p></jats:sec>

Exploring a New Entity of Single-Agent Pembrolizumab-Associated Hypophysitis

“…In our patient, three pituitary axes were affected: the adrenocorticotropic, thyroid and gonadotrophic axes. This is a rather rare presentation reported in three other patients in the currently available literature [20][21][22]27]. The time to onset was relatively short and ranged from three to nine months and two of the patients were diagnosed with melanoma [14].…”

“…Defects of the neurohypophysis are mainly reported in the context of pituitary metastasis [4]. Ascertainment of secondary adrenal failure used different testing strategies, including morning cortisol and ACTH [9,[11][12]15,[17][18][19][20][21][22][23][24][25][26][27], short Synacthen test [12,[16][17][18]21] and corticotropin-releasing hormone (CRH) stimulation test [12,16,24]. In our patient, three pituitary axes were affected: the adrenocorticotropic, thyroid and gonadotrophic axes.…”

“…In most cases, pembrolizumab was continued [9,17,25]. In some instances, this was after a transient interruption [20,23].…”

Differential expression of zinc finger CCHC-type superfamily proteins in thyroid carcinoma and their associations with tumor immunity

“…The correlation analysis showed that the ZCCHC gene family was associated with immune function in THCA, which was consistent with the results of previous studies, showing that ZCCHCs were associated with immunity. For example, ZCCHC17 is identified as a novel marker for the diagnosis and prognostic assessment of hepatocellular carcinoma (HCC) by regulating the immune cells in the tumor microenvironment (TME) of HCC patients, with specific reference value for immunotherapy of HCC, suggesting that ZCCHCs are associated with immunity [ 32 , 40 ]. Both GO and PPI network analyses suggested that the ZCCHC gene family probably functioned by regulating other proteins through metabolic pathways such as zinc ion binding and transition metal ion binding.…”

Endocrine toxicity of cancer immunotherapy: clinical challenges

“…The development of autoantibodies has been described in a number of IRAEs, including diabetes and hypophysitis ( 31 , 32 , 33 ). Two studies have now reported the development of auto-antibodies in hypophysitis ( 34 , 35 ), although notably there was no common antibodies described, and both studies included patients with both ipilimumab hypophysitis and the more limited ACTH deficiency with nivolumab or pembrolizumab. A further study suggested that hypophysitis was more common in certain HLA types, most notably DR15 ( 36 ), although again the hypophysitis cohort was heterogeneous.…”