Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors
Abstract PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has i...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-02-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-023-00788-9 |
| _version_ | 1811171831939334144 |
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| author | Deepti Gadi Stephen P. Martindale Pui Yan Chiu Jasneet Khalsa Pei-Hsuan Chen Stacey M. Fernandes Zixu Wang Svitlana Tyekucheva John-Hanson Machado David C. Fisher Philippe Armand Matthew S. Davids Scott Rodig Barbara Sherry Jennifer R. Brown |
| author_facet | Deepti Gadi Stephen P. Martindale Pui Yan Chiu Jasneet Khalsa Pei-Hsuan Chen Stacey M. Fernandes Zixu Wang Svitlana Tyekucheva John-Hanson Machado David C. Fisher Philippe Armand Matthew S. Davids Scott Rodig Barbara Sherry Jennifer R. Brown |
| author_sort | Deepti Gadi |
| collection | DOAJ |
| description | Abstract PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation. We further demonstrate directly using intracellular flow cytometry that autoimmune toxicity in patients is associated with higher absolute numbers of CD4 and CD8 T cells with Th17 differentiation in peripheral blood prior to therapy, and that gastrointestinal tissues from patients with active autoimmune complications of PI3Kδ inhibitors show infiltration with Th17+ T cells. These same tissues show depletion of Tregs as compared to CLL patients without toxicity, suggesting that loss of Tregs may be permissive for Th17 activation to lead to autoimmune toxicity. Clinical trials to restore this balance are warranted. |
| first_indexed | 2024-04-10T17:21:46Z |
| format | Article |
| id | doaj.art-94914f0b3bca45c9ad51c3edd14b1ac9 |
| institution | Directory Open Access Journal |
| issn | 2044-5385 |
| language | English |
| last_indexed | 2024-04-10T17:21:46Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj.art-94914f0b3bca45c9ad51c3edd14b1ac92023-02-05T12:05:13ZengNature Publishing GroupBlood Cancer Journal2044-53852023-02-0113111010.1038/s41408-023-00788-9Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitorsDeepti Gadi0Stephen P. Martindale1Pui Yan Chiu2Jasneet Khalsa3Pei-Hsuan Chen4Stacey M. Fernandes5Zixu Wang6Svitlana Tyekucheva7John-Hanson Machado8David C. Fisher9Philippe Armand10Matthew S. Davids11Scott Rodig12Barbara Sherry13Jennifer R. Brown14Department of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteCenter for Immunology & Inflammation, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell HealthDepartment of Medical Oncology, Dana-Farber Cancer InstituteCenter for Immuno-Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Data Sciences, Dana-Farber Cancer InstituteDepartment of Data Sciences, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteCenter for Immuno-Oncology, Dana-Farber Cancer InstituteCenter for Immunology & Inflammation, Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell HealthDepartment of Medical Oncology, Dana-Farber Cancer InstituteAbstract PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity, despite promising efficacy and evidence that toxicity is associated with improved clinical outcomes. Prior phenotypic evaluation by CyTOF has identified increases in activated CD8 T cells with activation of Th17 T cells, as well as decreases in Tregs, particularly in patients with toxicity. Here we sought to further understand the effects of idelalisib and duvelisib in vitro, and demonstrate that both idelalisib and duvelisib can inhibit T cell proliferation as well as Th1 and Treg differentiation in vitro, while promoting Th2 and Th17 differentiation. We further demonstrate directly using intracellular flow cytometry that autoimmune toxicity in patients is associated with higher absolute numbers of CD4 and CD8 T cells with Th17 differentiation in peripheral blood prior to therapy, and that gastrointestinal tissues from patients with active autoimmune complications of PI3Kδ inhibitors show infiltration with Th17+ T cells. These same tissues show depletion of Tregs as compared to CLL patients without toxicity, suggesting that loss of Tregs may be permissive for Th17 activation to lead to autoimmune toxicity. Clinical trials to restore this balance are warranted.https://doi.org/10.1038/s41408-023-00788-9 |
| spellingShingle | Deepti Gadi Stephen P. Martindale Pui Yan Chiu Jasneet Khalsa Pei-Hsuan Chen Stacey M. Fernandes Zixu Wang Svitlana Tyekucheva John-Hanson Machado David C. Fisher Philippe Armand Matthew S. Davids Scott Rodig Barbara Sherry Jennifer R. Brown Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors Blood Cancer Journal |
| title | Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors |
| title_full | Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors |
| title_fullStr | Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors |
| title_full_unstemmed | Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors |
| title_short | Circulating Th17 T cells at treatment onset predict autoimmune toxicity of PI3Kδ inhibitors |
| title_sort | circulating th17 t cells at treatment onset predict autoimmune toxicity of pi3kδ inhibitors |
| url | https://doi.org/10.1038/s41408-023-00788-9 |
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