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Multiomics analysis of immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors

ABSTRACT: Immune checkpoint inhibitors (ICIs) are a standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events (irAEs). Proteomic analysis and multiplex cytokine/chemokine assay from serum at baseline and at irAEs onset in 82 patients indicated aberrant T-cell activity with differential expression of Type I and III immune signatures. This was in line with an increase in the proportions of monocytes and decrease of IL-17A producing CD4+ T-cells in the peripheral blood in single cell RNA sequencing. Multiplex immunohistochemistry on ICI-induced skin rash and inflamed colon showed increase in the proportion of CD4+ T-cells with IL-17A expression. Anti-IL17A antagonistic mAbs were administered in two patients with severe myocarditis, colitis and skin rash with resolution of the irAE. This study demonstrates the potential role of Type III CD4+ T-cells in the irAEs development and provides proof-of-principle evidence to support a clinical trial examining anti-IL17A in their management.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227001 | GEO | 2023/12/01

REPOSITORIES: GEO

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Checkpoint blockade-induced dermatitis and colitis are dominated by tissue resident memory T cells and Th1/Tc1 cytokines

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2022-08-08 | GSE210037 | GEO

Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (human)]

Project description:Checkpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+ RORt+ CD4+ (T helper 17 or Th17) and gamma delta 17 (T17) T cells promote thyroid IrAE development. In parallel, Th17 and T17 cells were similarly expanded in cancer patients treated with ICI. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in a mouse tumor model did not reduce ICI anti-tumor efficacy and indeed showed a trend toward enhancement. These studies suggest that targeting Th17 and 17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.

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Inhibition of IL-17A Protects against Thyroid Immune-related Adverse Events while Preserving Checkpoint Inhibitor Anti-tumor Efficacy [RNA-seq (murine)]

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