Inhibition of IL-17A Protects against Thyroid Immune-related Adverse Events while Preserving Checkpoint Inhibitor Anti-tumor Efficacy

• Published in: The Journal of immunology (1950) 2022-07, 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
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2200244

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. Here 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 gamma delta T (γδT17) cells were increased in tumor-free mice, whereas adaptive T helper 17 (Th17) cells were also prominent in tumor-bearing mice, following ICI treatment. Furthermore, antibody-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 anti-tumor efficacy. These studies suggest that targeting Th17 and γδT17 function via the IL-17A axis may reduce IrAEs without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address Type 3 immune-mediated IrAEs.