Clonally expanded, thyrotoxic effector CD8 ⁺ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis

Abstract

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto’s thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6 + CD8 + T cells (effector CD8 + T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (T FH ) and T peripheral helper (T PH ) cells, as a driver of these thyrotoxic effector CD8 + T cells. In the presence of IL-21, human CD8 + T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.

Immune‐related adverse events in non‐small cell lung cancer: Occurrence, mechanisms and therapeutic strategies

“…Consequently, as has been previously hypothesised, PD‐1 inhibitors could potentially disrupt T fh cell function, resulting in the generation of aberrant B cells and ultimately leading to the occurrence of irAEs 18,114 . More recently, Lechner et al 97 . identified the infiltration of both T peripheral helper (T ph ) and T fh cells into ICI‐related thyroiditis tissue in patients with NSCLC and other types of tumours.…”

“…Historical data further indicate an escalated prevalence of CD8+ T cells in lung samples from NSCLC patients who developed CIP after nivolumab, highlighting the crucial role of antigen cross‐reactivity 96 . Furthermore, Lechner et al 97 . found a clonally expanded segment of cytotoxic C‐X‐C motif chemokine receptor 6 (CXCR6)+ CD8+ T cells in thyroid tissue, a population characterised by interferon‐γ (IFN‐γ) and granzyme B upregulation and spurred on by interleukin (IL)‐21, which was indicative of ICI‐induced thyroiditis in NSCLC and other cancer types 97 .…”

“…identified the infiltration of both T peripheral helper (T ph ) and T fh cells into ICI‐related thyroiditis tissue in patients with NSCLC and other types of tumours. They proposed a potential mechanism in vivo in which IL‐21+ T fh and T ph cells might significantly contribute to ICI‐induced autoimmunity by augmenting the effector characteristics of CD8+ T cells 97 . Specifically, recombinant IL‐21 has been shown to activate CD8+ effectors expressing CXCR6, GZMB and IFN‐γ, thereby enhancing thyrotoxic activity in mice.…”

Stocking the toolbox—Using preclinical models to understand the development and treatment of immune checkpoint inhibitor‐induced immune‐related adverse events

“…β2m −/− melanoma, were transplanted into autoimmune-prone NOD mice receiving ICI treatment to assess the impact of anti-IL-17A treatment toward both irAEs and anti-tumor immunity. 63 Notably, anti-IL-17A was able to protect against the development of thyroid irAEs, while maintaining the robust tumor control provided by combination anti-PD-1 and anti-CTLA-4 treatment. 34 While this allows for the coordinated assessment of anti-tumor immunity and autoimmunity in response to ICI treatment alongside an anti-irAE therapy, it remains unclear whether using a tumor generated in an alternate mouse strain with defective antigen presentation is an appropriate system for monitoring immune-mediated responses reflective of clinical conditions.…”

“…34,46,70 The pleiotropic nature by which cytokines elicit their effects Increased polarization of these IL-21-producing CD4 + T cells was able to drive clonal expansion of cytotoxic CD8 + T cells that could elicit thyroid damage in ICI-treated mice, an effect that was lost in mice deficient for IL-21 signaling. 63 The effect toward anti-tumor immunity was not examined in the presence of defective IL-21…”