Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities

Tahir, Salahaldin A.; Gao, Jianjun; Miura, Yuji; Blando, Jorge; Tidwell, Rebecca S. Slack; Zhao, Hao; Subudhi, Sumit K.; Tawbi, Hussein A.; Keung, Emily Z.; Wargo, Jennifer A.; Allison, James P.; Sharma, Padmanee

doi:10.1073/pnas.1908079116

Cited by 155 publications

(145 citation statements)

References 44 publications

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“…Some researchers managed to find organ-specific autoantibodies, but this is more likely due to the development of a chronic disease. Researchers of the Salahaldin A. Tahira group determined the organ-specific antibodies in the development of hypophysitis, namely anti-GNAL and anti-ITM2B, and pneumonitis, anti-CD74 [ 117 ], while antibodies to thyroperoxidase are used for autoimmune thyroiditis diagnosis [ 118 ]. Despite the contradictory results, some authors suggest using ANA, anti-smooth muscle antibody, for the diagnosis of liver damage.…”

Section: Classical Examples Of the Asia Syndromementioning

confidence: 99%

Classical Examples of the Concept of the ASIA Syndrome

et al. 2020

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Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was first introduced in 2011 by Shoenfeld et al. and encompasses a cluster of related immune mediated diseases, which develop among genetically prone individuals as a result of adjuvant agent exposure. Since the recognition of ASIA syndrome, more than 4400 documented cases have been reported so far, illustrated by heterogeneous clinical manifestations and severity. In this review, five enigmatic conditions, including sarcoidosis, Sjögren’s syndrome, undifferentiated connective tissue disease, silicone implant incompatibility syndrome (SIIS), and immune-related adverse events (irAEs), are defined as classical examples of ASIA. Certainly, these disorders have been described after an adjuvant stimulus (silicone implantation, drugs, infections, metals, vaccines, etc.) among genetically predisposed individuals (mainly the HLA-DRB1 and PTPN22 gene), which induce an hyperstimulation of the immune system resulting in the production of autoantibodies, eventually leading to the development of autoimmune diseases. Circulating autonomic autoantibodies in the sera of patients with silicone breast implants, as well as anatomopathological aspects of small fiber neuropathy in their skin biopsies have been recently described. To our knowledge, these novel insights serve as a common explanation to the non-specific clinical manifestations reported in patients with ASIA, leading to the redefinition of the ASIA syndrome diagnostic criteria.

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Section: Classical Examples Of the Asia Syndromementioning

confidence: 99%

Classical Examples of the Concept of the ASIA Syndrome

et al. 2020

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“…In regard to ICI-mediated hypophysitis, one study showed serial increases in autoantibodies to the proteins GNAL and ITM2B in patients treated with ipilimumab. ZCCHC8 autoantibodies were not increased in this discovery cohort (9). Our study showed that patient 1 had a 2.4-fold increase in ITM2B and patient 2 had no ITM2B increases.…”

Section: Discussionmentioning

confidence: 42%

“…These arrays identify patterns of autoantibody response against a large number of antigens during the course of development of diseases, such as autoimmunity or malignancy (4)(5)(6). Protoarray studies have shown that certain autoantibodies may predict ICI toxicity (7,8), but only one recent study has examined autoantibody changes in hypophysitis specifically, showing increases in the autoantibodies GNAL and ITM2B in 8 patients (including melanoma, prostate cancer, and renal cell carcinoma) (9).…”

Section: Introductionmentioning

confidence: 99%

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

Leiter

Gnjatic

Fowkes

et al. 2020

AACE Clinical Case Reports

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Objective: 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. Methods: 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. Results: 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. Conclusion: 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.

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“…Autoantibodies against TSH-, FSH-, or ACTH-producing cells have been detected in patients with ipilimumab-induced hypophysitis (45). A screening using cDNA expression libraries of the plasma samples identified anti-olfactory type G-protein alpha-activating activity polypeptide (GNAL) antibody and anti-integral membrane protein 2B (ITM2B) antibody in ICI-induced hypophysitis (48). Although the pathophysiological role of these antibodies is still unclarified, it has been suggested that the anti-GNAL autoantibody has the potential to act as both a predictive and an on-treatment biomarker for ICI-induced hypophysitis, whereas the anti-ITM2B autoantibody has the potential to act as an on-treatment biomarker for ICI-induced hypophysitis (48).…”

Section: Ici-induced Hypophysitismentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Autoimmune hypopituitarism: novel mechanistic insights

Takahashi¹

2020

European Journal of Endocrinology

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Hypopituitarism is caused by various insults to the pituitary, such as hypothalamic and pituitary tumors, inflammation, autoimmunity, vascular injury, genetic abnormalities, irradiation, and trauma. Recently, it has been found that autoimmunity to the pituitary involves many pathological conditions associated with specific or non-specific hormone deficiencies in the gland. This review discusses the recent findings on the underlying mechanism of autoimmune hypopituitarism particularly of lymphocytic hypophysitis, IgG4-related hypophysitis, immune checkpoint inhibitor-induced hypophysitis, anti-PIT-1 hypophysitis, and isolated ACTH deficiency.

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Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities

Cited by 155 publications

References 44 publications

Classical Examples of the Concept of the ASIA Syndrome

Classical Examples of the Concept of the ASIA Syndrome

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

MECHANISMS IN ENDOCRINOLOGY: Autoimmune hypopituitarism: novel mechanistic insights

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