Inhibition of IL-17A Protects against Thyroid Immune-Related Adverse Events while Preserving Checkpoint Inhibitor Antitumor Efficacy

Immune checkpoint inhibitor (ICI) immunotherapy leverages the body's own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune-related adverse events (IrAEs) may lead to treatment interruption, permanent organ dysfunction, hospi...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2022-08, Vol.209 (4), p.696-709
Main Authors: Lechner, Melissa G, Cheng, Mandy I, Patel, Anushi Y, Hoang, Aline T, Yakobian, Natalie, Astourian, Michael, Pioso, Marissa S, Rodriguez, Eduardo D, McCarthy, Ethan C, Hugo, Willy, Angell, Trevor E, Drakaki, Alexandra, Ribas, Antoni, Su, Maureen A
Format: Article
Language:English
Subjects:
Animals
Drug-Related Side Effects and Adverse Reactions
Immunotherapy
Interleukin-17
Mice
Neoplasms - pathology
Thyroid Gland - pathology
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Summary:Immune checkpoint inhibitor (ICI) immunotherapy leverages the body's own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune-related adverse events (IrAEs) may lead to treatment interruption, permanent organ dysfunction, hospitalization, and premature death. Thyroiditis is one of the most common IrAEs, but the cause of thyroid IrAEs remains unknown. In this study, we use a new, physiologically relevant mouse model of ICI-associated autoimmunity to identify a key role for type 3 immune cells in the development of thyroid IrAEs. Multiple lineages of IL-17A-producing T cells expand in thyroid tissue with ICI treatment. Intrathyroidal IL-17A-producing innate-like γδT17 cells were increased in tumor-free mice, whereas adaptive Th17 cells were also prominent in tumor-bearing mice, following ICI treatment. Furthermore, Ab-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice with and without tumor challenge. Finally, combination of IL-17A neutralization with ICI treatment in multiple tumor models did not reduce ICI antitumor efficacy. These studies suggest that targeting Th17 and γδT17 cell function via the IL-17A axis may reduce IrAEs without impairing ICI antitumor efficacy and may be a generalizable strategy to address type 3 immune-mediated IrAEs.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.2200244