Interleukin-21 Identified as Potential New Therapeutic Target to Prevent Endocrine Autoimmune Adverse Effects From Cancer Immunotherapy

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Researchers have discovered that interleukin-21 may be a potential therapeutic target to help reduce the endocrine autoimmune adverse effects and prevent the thyroid autoimmunity experienced by patients with cancer undergoing treatment with immune checkpoint inhibitors, according to a novel study published by Lechner et al in Science Translational Medicine. The findings suggested that CXCR6-positive interferon gamma–positive cytotoxic CD8-positive T cells—a group of immune cells that have demonstrated strong killing activity—could be controlled by interleukin-21 and may play a central role in this autoimmune attack.


Interleukin-21 is a soluble molecule involved in activating the immune system. Immune checkpoint inhibitors are capable of harnessing the power of the immune system to fight cancer cells and have shown remarkable success in treating multiple types of advanced cancers. While this type of therapy has changed the face of cancer treatment, increased immune activation can result in unwanted autoimmune attacks on healthy tissues. Such immune-related adverse events can occur in up to 60% of patients treated with immune checkpoint inhibitors and can contribute to treatment interruption, hospitalizations, and even premature death.

The cause of these autoimmune toxicities remains largely unknown, and there are presently no effective treatments to prevent or reverse these endocrine autoimmune adverse effects during cancer immunotherapy—which almost universally results in permanent organ damage and a lifelong requirement for hormone replacement therapy.

“Our study is the first to provide an in-depth look at the cause of [immune] checkpoint inhibitor–associated thyroid autoimmunity in humans and highlights a potential pathway for preventing this treatment-related autoimmune toxicity,” explained lead study author Melissa Lechner, MD, PhD, Assistant Professor of Medicine in the Division of Endocrinology, Diabetes, and Metabolism at the David Geffen School of Medicine at the University of California, Los Angeles. 

Study Methods and Results

In the new study, the researchers sequenced the single-cell RNA of thyroid specimens from patients to investigate the cause of the endocrine autoimmune adverse effects that occur during treatment with immune checkpoint inhibitors. The researchers then demonstrated that clonally expanded effector CD8-positive T cells expressing CXCR6, granzyme B, and interferon gamma were increased in patients who experienced endocrine autoimmune adverse events. Further, interleukin-21 from CD4-positive T cells was found to drive the thyrotoxic function of these CD8-positive T cells. In mouse models, the researchers were able to prove that inhibition of interleukin-21 prevented immune checkpoint inhibitor–associated thyroid autoimmunity.  


The new findings highlighted potential immune pathways that can be targeted to reduce immunotherapy toxicities in patients with cancer. Understanding how these toxicities may develop in patients treated with immunotherapy could help researchers develop strategies to reduce these side effects and make treatments safer. In addition, mechanisms driving cancer immunotherapy–related autoimmunity may be shared with spontaneous autoimmune diseases—such as type 1 diabetes and Hashimoto's thyroiditis. The researchers hope that their findings can help identify targets for the treatment of a broad number of autoimmune diseases.

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