Newly discovered pathway provides potential key to prevent adverse effects of immunotherapy

BioTechniques News
Aisha Al-Janabi

Researchers identify a possible therapeutic target to prevent endocrine autoimmune adverse effects during checkpoint inhibitor immunotherapy.

A study led by researchers at the University of California, Los Angeles (CA, USA) has revealed that interleukin-21 (IL-21) plays a role in the autoimmune attack that can occur following checkpoint-inhibitor cancer therapy, finding it controls the activity of CD8+ T cells. The researchers suggest that this pathway could be a potential therapeutic target to reduce endocrine autoimmune side effects.

Checkpoint inhibitors are a type of immunotherapy that block checkpoint proteins on the surface of T cells, preventing them from being turned ‘off’ in the tumour microenvironment and allowing them to kill cancer cells. This has proven to be successful in treating different types of advanced cancers; however, the increased immune activation can result in an autoimmune attack on healthy tissues, causing complications in up to 60% of patients treated with checkpoint inhibitors.

This autoimmune toxicity can result in organ damage and a lifelong requirement for hormone replacement therapy. The cause is largely unknown and there are no effective treatments currently available.

To understand the cause of immunotherapy-related autoimmune adverse effects, the researchers of this study focussed on immune checkpoint inhibitor thyroiditis (ICI-thyroiditis), an immune-related adverse effect that can result in the destruction of thyroid tissue.

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Using single-cell RNA sequencing, the researchers compared immune infiltrates present in thyroid specimens from individuals with ICI-thyroiditis to samples from those with spontaneous autoimmune Hashimoto’s thyroiditis and those with no thyroid disease. This revealed increased amounts of clonally expanded effector CD8+ T cells that express CXCR6+ Granzyme B+ and interferon gamma+ in samples from those with ICI-thyroiditis, but not in the other sample types. This is a group of immune cells with strong cell-killing activity.

The study also found that IL-21 from CD4+ T helper cells, a soluble molecule that has regulatory effects on cells of the immune system, drives the thyrotoxic function of CD8+ T cells. These results were validated in vivo by inhibiting IL-21 in a mouse model. This inhibition prevented checkpoint inhibitor-associated thyroid autoimmunity, indicating that IL-21 could be a possible therapeutic target to reduce endocrine autoimmune side effects.

“Our study is the first to provide an in-depth look at the cause of checkpoint inhibitor-associated autoimmunity in humans and highlights a potential pathway for preventing this treatment-related autoimmune toxicity,” said Melissa Lechner, the first author of the study.

These results could lead to a strategy to make checkpoint inhibitor immunotherapy treatments safer and reduce endocrine autoimmune side effects. Additionally, this mechanism could be shared with some spontaneous immune diseases, like type 1 diabetes, meaning these findings could also lead to new therapeutic targets for a range of autoimmune diseases.

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