Journal article
Clonally expanded, thyrotoxic effector CD8 + T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis
Science translational medicine, v 15(696), eadg0675
17 May 2023
PMID: 37196065
Featured in Collection : UN Sustainable Development Goals @ Drexel
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
) and T peripheral helper (T
) 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.
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Details
- Title
- Clonally expanded, thyrotoxic effector CD8 + T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis
- Creators
- Melissa G Lechner - Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAZikang Zhou - Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAAline T Hoang - Drexel UniversityNicole Huang - Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAJessica Ortega - Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USALauren N Scott - Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAHo-Chung Chen - Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAAnushi Y Patel - Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USARana Yakhshi-Tafti - Rosalind Franklin Medical School, Chicago, IL 60064, USAKristy Kim - UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAWilly Hugo - Division of Dermatology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAPouyan Famini - Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAAlexandra Drakaki - Division of Hematology and Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USAAntoni Ribas - Division of Hematology and Oncology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USATrevor E Angell - Division of Endocrinology and Diabetes, USC Keck School of Medicine, Los Angeles, CA 90033, USAMaureen A Su - Division of Pediatric Endocrinology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA
- Publication Details
- Science translational medicine, v 15(696), eadg0675
- Publisher
- American Association for the Advancement of Science
- Grant note
- P30 CA016042 / NCI NIH HHS K08 DK129829 / NIDDK NIH HHS R01 CA236910 / NCI NIH HHS R35 CA197633 / NCI NIH HHS R01 DK119445 / NIDDK NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- College of Medicine
- Web of Science ID
- WOS:001000701200006
- Scopus ID
- 2-s2.0-85159766401
- Other Identifier
- 991022207173304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology
- Medicine, Research & Experimental