IL-21: The Ultimate Strategy to Fight Side Effects from Immunotherapy

IL-21, a soluble molecule associated with immune system activation, could be a therapeutic target to help minimize endocrine autoimmune adverse effects of checkpoint inhibitor cancer therapy (1^✔ ✔Trusted Source
Clonally expanded, thyrotoxic effector CD8+ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis

Go to source). The researchers discovered that a subset of CD8+ immune cells known as CXCR6+ IFN- cytotoxic CD8+ T cells play a critical role in this autoimmune onslaught. They also discovered that IL-21 regulated the activation of these CD8+ cells and that inhibiting IL-21 reduced thyroid autoimmunity.

Checkpoint Inhibitors Associated with Thyroid Autoimmunity

"Our 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," said 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 and first author of the study.

Checkpoint inhibitors are a sort of cancer therapy that uses the immune system's power to combat cancer cells and has demonstrated exceptional success in treating a variety of advanced tumors. While this type of therapy has transformed cancer treatment, greater immune activation can result in an undesirable autoimmune attack on healthy tissues. Such immune-related side effects occur in up to 60% of individuals receiving the therapy and can lead to treatment interruptions, hospitalizations, and even premature death.

The exact source of this autoimmune toxicity is uncertain. There are currently no viable treatments to avoid or correct these endocrine immune side effects of cancer immunotherapy, which virtually often result in chronic organ damage and a lifelong need for hormones.

Single RNA Sequencing for Thyroid Specimens

The team used single-cell RNA sequencing of patient thyroid specimens to study the source of autoimmune toxicities following checkpoint inhibitor cancer therapy. The researchers subsequently discovered that people with thyroid adverse events have increased clonally-expanded effector CD8+ T lymphocytes expressing CXCR6+ Granzyme B and interferon-. Furthermore, they discovered that IL-21 produced by CD4+ T helper cells is responsible for the thyrotoxic action of these CD8+ T cells, and that inhibiting IL-21 in a mouse model reduced checkpoint inhibitor-associated thyroid autoimmunity.

The findings point to potential immunological mechanisms that can be addressed to minimize the toxicity of immunotherapy in patients. Understanding how autoimmune toxicities arise in cancer immunotherapy patients can aid researchers in developing techniques to decrease these side effects, making treatment safer.

Furthermore, the processes behind cancer immunotherapy-related autoimmunity may be similar to those found in spontaneous autoimmune illnesses such as type 1 diabetes and Hashimoto's thyroiditis. As a result, the findings of this study can assist researchers in identifying targets for the therapy of a wide range of autoimmune illnesses.

Reference:

1. Clonally expanded, thyrotoxic effector CD8+ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis - (https://pubmed.ncbi.nlm.nih.gov/37196065/)

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Source-Medindia