A targetable type III immune response with increase of IL-17A expressing CD4+ T cells is associated with immunotherapy-induced toxicity in melanoma
Immune checkpoint inhibitors are standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events. Proteomic analyses and multiplex cytokine and chemokine assays from serum at baseline and at the adverse event onset indicated aberrant T cell activity with differential expression of type I and III immune signatures. This was in line with the finding of an increase in the proportion of CD4<sup>+</sup> T cells with IL-17A expression at the adverse event onset in the peripheral blood using flow cytometry. Multiplex immunohistochemistry and spatial transcriptomics on immunotherapy-induced skin rash and colitis showed an increase in the proportion of CD4<sup>+</sup> T cells with IL-17A expression. Anti-IL-17A was administered in two patients with mild myocarditis, colitis and skin rash with resolution of the adverse events. This study highlights the potential role of type III CD4<sup>+</sup> T cells in adverse event development and provides proof-of-principle evidence for a clinical trial using anti-IL-17A for treating adverse events.
Authors
- Annalisa Saltari (ORCID: https://orcid.org/0000-0002-8621-4039)
- Florentia Dimitriou (ORCID: https://orcid.org/0000-0003-4529-3372)
- Olivier Michielin (ORCID: https://orcid.org/0000-0003-4926-6355)
- Ralf Gutzmer (ORCID: https://orcid.org/0000-0001-7921-2820)
- Federica Sella (ORCID: https://orcid.org/0000-0002-0805-0905)
- Katrin Schaper‐Gerhardt (ORCID: https://orcid.org/0000-0002-5318-0039)
- Mitchell Paul Levesque (ORCID: https://orcid.org/0000-0001-5902-9420)
- Veronika Haunerdinger (ORCID: https://orcid.org/0000-0002-6184-8182)
- Christian M. Matter (ORCID: https://orcid.org/0000-0002-8124-1767)
- Ramon Staeger (ORCID: https://orcid.org/0000-0002-9283-9596)
- Phil F. Cheng (ORCID: https://orcid.org/0000-0003-2940-006X)
- Burkhard Becher (ORCID: https://orcid.org/0000-0002-1541-7867)
- Daniela Mihic‐Probst (ORCID: https://orcid.org/0000-0002-2215-9958)
- Georgina Venetia Long (ORCID: https://orcid.org/0000-0001-8894-3545)
- Aizhan Tastanova (ORCID: https://orcid.org/0000-0003-1120-5610)
- Susanne Dettwiler (ORCID: https://orcid.org/0000-0003-1169-6296)
- Reinhard Dummer (ORCID: https://orcid.org/0000-0002-2279-6906)
- Christian Urban (ORCID: https://orcid.org/0000-0003-0253-5386)
Institutions
- The University of Sydney (AU)
- University of Zurich (CH)
- Royal North Shore Hospital (AU)
- Medizinische Hochschule Hannover (DE)
- ETH Zurich (CH)
- University Hospital of Zurich (CH)
- University Hospital of Geneva (CH)
- Melanoma Institute Australia (AU)
- Johannes Wesling Klinikum Minden (DE)
- Ruhr University Bochum (DE)
Publication Details
- Journal
- Nature Cancer
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1038/s43018-024-00810-4
- Citations
- 28
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 7.91
Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Gottfried und Julia Bangerter-Rhyner-Stiftung
- Universität Zürich
- Schweizerische Akademie der Medizinischen Wissenschaften