Inhibition of IL-21 Blocks Autoimmune Toxicity

Autoimmune toxicity is a significant side effect associated with immune checkpoint inhibitor (ICI) therapy used in the treatment of cancer. Immune checkpoint inhibitors, such as anti-PD-1 (programmed cell death protein 1) and anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibodies, have revolutionized cancer treatment by unleashing the body’s immune system to attack cancer cells. However, by modulating the immune response, these therapies can also lead to the development of autoimmune toxicities. Autoimmune toxicity occurs when the immune system mistakenly attacks healthy cells and tissues in various organs of the body, causing inflammation and damage. The specific organs affected and the severity of the toxicities can vary among individuals. Common sites of autoimmune toxicity include the skin, gastrointestinal tract, liver, endocrine glands, lungs, kidneys, and nervous system. The mechanism underlying autoimmune toxicity is complex and not yet fully understood. Immune checkpoints, such as PD-1 and CTLA-4, play a crucial role in maintaining self-tolerance and preventing excessive immune activation. Cancer cells exploit these checkpoints to evade immune recognition and destruction. Immune checkpoint inhibitors disrupt this evasion mechanism, allowing the immune system to recognize and attack cancer cells. However, this immune activation can also result in the immune system attacking normal cells and tissues.

Checkpoint inhibitors are a type of cancer therapy that harnesses the power of the immune system to fight cancer cells and have shown to have remarkable success in treating multiple types of advanced cancers. While this type of therapy has changed the face of cancer treatment, with increased immune activation can come unwanted autoimmune attack on healthy tissues. Such immune related adverse events occur in up to 60% of patients treated with the therapy and can contribute to treatment interruption, hospitalizations, and even premature death. The cause of these autoimmune toxicities remains largely unknown. Presently there are no effective treatments to prevent or reverse these endocrine immune adverse effects during cancer immunotherapy, which almost universally result in permanent organ damage and lifelong requirement for hormone replacement therapy.

In a new study published in the peer-reviewed journal Science Translational Medicine, Zikang Zhou, Aline T Hoang, Nicole Huang, Jessica Ortega , Lauren N Scott, Ho-Chung Chen, Anushi Y Patel, Rana Yakhshi-Tafti , Kristy Kim , Willy Hugo, Pouyan Famini, Alexandra Drakaki, Antoni Ribas, Trevor E Angell, Maureen A Su and led by Dr. Melissa Lechner, an assistant professor of Medicine in the division of Endocrinology, Diabetes, and Metabolism at the David Geffen School of Medicine at UCLA demonstrated that IL-21, a soluble molecule involved in activating the immune system, can be a potential therapeutic target to help reduce endocrine autoimmune side effects caused by checkpoint inhibitor cancer therapy. The authors found that  a specific group of CD8+ immune cells with strong killing activity, called CXCR6+ IFN-γ cytotoxic CD8+ T cells, play a central role in this autoimmune attack. They also found the activity of these CD8+ cells were controlled by IL-21 and blocking IL-21 prevented thyroid autoimmunity.

The study is the first to provide an in-depth look at the cause of checkpoint inhibitor associated thyroid autoimmunity in humans and highlights a potential pathway for preventing this treatment-related autoimmune toxicity. To investigate the cause of autoimmune toxicities that occur during checkpoint inhibitor cancer therapy, the authors used single cell RNA sequencing of thyroid specimens from patients. The team then showed that clonally-expanded effector CD8+ T cells expressing CXCR6+ Granzyme B and interferon-γ are increased in individuals with thyroid adverse events. Furthermore, they found that IL-21 from CD4+ T helper cells drives the thyrotoxic function of these CD8+ T cells and that inhibition of IL-21 in a mouse model prevented checkpoint inhibitor-associated thyroid autoimmunity.

The findings highlight potential immune pathways that can be targeted to reduce immunotherapy toxicities in patients. Understanding how autoimmune toxicities develop in patients treated with cancer immunotherapy will help researchers develop strategies to reduce these side effects, making treatment 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 new study  findings are far reaching and can also help researchers identify targets for the treatment of a broad number of autoimmune diseases.