Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma
Background Immune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs are needed. In this study, we aimed to identify immune feature...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2024-01-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/12/1/e008056.full |
| _version_ | 1797326779513307136 |
|---|---|
| author | Siwen Hu-Lieskovan Ngan Nguyen Magdalena Kovacsovics-Bankowski John Hyngstrom Li-Chun Cheng Jordan P McPherson Umang Swami Matthew H Spitzer Johanna M Sweere Connor P Healy Natalia Sigal William D Chronister Shane A Evans John Marsiglio Berit Gibson Alyssa Erickson-Wayman Yoko S Derose Annaleah Larson Eliason Carlos O Medina Ramji Srinivasan |
| author_facet | Siwen Hu-Lieskovan Ngan Nguyen Magdalena Kovacsovics-Bankowski John Hyngstrom Li-Chun Cheng Jordan P McPherson Umang Swami Matthew H Spitzer Johanna M Sweere Connor P Healy Natalia Sigal William D Chronister Shane A Evans John Marsiglio Berit Gibson Alyssa Erickson-Wayman Yoko S Derose Annaleah Larson Eliason Carlos O Medina Ramji Srinivasan |
| author_sort | Siwen Hu-Lieskovan |
| collection | DOAJ |
| description | Background Immune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs are needed. In this study, we aimed to identify immune features detectable in peripheral blood and associated with the development of severe irAEs that required clinical intervention.Methods We used a 43-marker mass cytometry panel to characterize peripheral blood mononuclear cells from 28 unique patients with melanoma across 29 lines of ICI therapy before treatment (baseline), before the onset of irAEs (pre-irAE) and at the peak of irAEs (irAE-max). In the 29 lines of ICI therapy, 18 resulted in severe irAEs and 11 did not.Results Unsupervised and gated population analysis showed that patients with severe irAEs had a higher frequency of CD4+ naïve T cells and lower frequency of CD16+ natural killer (NK) cells at all time points. Gated population analysis additionally showed that patients with severe irAEs had fewer T cell immunoreceptor with Ig and ITIM domain (TIGIT+) regulatory T cells at baseline and more activated CD38+ CD4+ central memory T cells (TCM) and CD39+ and Human Leukocyte Antigen-DR Isotype (HLA-DR)+ CD8+ TCM at peak of irAEs. The differentiating immune features at baseline were predominantly seen in patients with gastrointestinal and cutaneous irAEs and type 1 diabetes. Higher frequencies of CD4+ naïve T cells and lower frequencies of CD16+ NK cells were also associated with clinical benefit to ICI therapy.Conclusions This study demonstrates that high-dimensional immune profiling can reveal novel blood-based immune signatures associated with risk and mechanism of severe irAEs. Development of severe irAEs in melanoma could be the result of reduced immune inhibitory capacity pre-ICI treatment, resulting in more activated TCM cells after treatment. |
| first_indexed | 2024-03-08T06:29:05Z |
| format | Article |
| id | doaj.art-33adf4f87d5845b590a6128eac8e0678 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-08T06:29:05Z |
| publishDate | 2024-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-33adf4f87d5845b590a6128eac8e06782024-02-03T12:15:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-01-0112110.1136/jitc-2023-008056Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanomaSiwen Hu-Lieskovan0Ngan Nguyen1Magdalena Kovacsovics-Bankowski2John Hyngstrom3Li-Chun Cheng4Jordan P McPherson5Umang Swami6Matthew H Spitzer7Johanna M Sweere8Connor P Healy9Natalia Sigal10William D Chronister11Shane A Evans12John Marsiglio13Berit Gibson14Alyssa Erickson-Wayman15Yoko S Derose16Annaleah Larson Eliason17Carlos O Medina18Ramji Srinivasan199Jonsson Comprehensive Cancer Center, Los Angeles, CA, USATeiko.bio Inc, Salt Lake City, Utah, USAAff1 grid.240531.1000000040456863XEarle A. Chiles Research Institute, Providence Cancer CenterPortland Providence Medical Center 4805 NE Glisan St 97213 PortlandOregon USAHuntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USANational Institute of Cancer Research, National Health Research Institutes, Zhunan, Miaoli, TaiwanDepartment of Pharmacy, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USAMedicine, University of Utah Health, Huntsman Cancer Institute, Salt Lake City, Utah, USA2Genentech Inc, South San Francisco, CA, USATeiko.bio Inc, Salt Lake City, Utah, USATeiko.bio Inc, Salt Lake City, Utah, USATeiko.bio Inc, Salt Lake City, Utah, USATeiko.bio Inc, Salt Lake City, Utah, USATeiko.bio Inc, Salt Lake City, Utah, USAThe University of Utah School of Medicine, Salt Lake City, Utah, USAHuntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USAHuntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USAHuntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USAThe University of Utah School of Medicine, Salt Lake City, Utah, USATeiko.bio Inc, Salt Lake City, Utah, USATeiko.bio Inc, Salt Lake City, Utah, USABackground Immune-related adverse events (irAEs) are major barriers of clinical management and further development of immune checkpoint inhibitors (ICIs) for cancer therapy. Therefore, biomarkers associated with the onset of severe irAEs are needed. In this study, we aimed to identify immune features detectable in peripheral blood and associated with the development of severe irAEs that required clinical intervention.Methods We used a 43-marker mass cytometry panel to characterize peripheral blood mononuclear cells from 28 unique patients with melanoma across 29 lines of ICI therapy before treatment (baseline), before the onset of irAEs (pre-irAE) and at the peak of irAEs (irAE-max). In the 29 lines of ICI therapy, 18 resulted in severe irAEs and 11 did not.Results Unsupervised and gated population analysis showed that patients with severe irAEs had a higher frequency of CD4+ naïve T cells and lower frequency of CD16+ natural killer (NK) cells at all time points. Gated population analysis additionally showed that patients with severe irAEs had fewer T cell immunoreceptor with Ig and ITIM domain (TIGIT+) regulatory T cells at baseline and more activated CD38+ CD4+ central memory T cells (TCM) and CD39+ and Human Leukocyte Antigen-DR Isotype (HLA-DR)+ CD8+ TCM at peak of irAEs. The differentiating immune features at baseline were predominantly seen in patients with gastrointestinal and cutaneous irAEs and type 1 diabetes. Higher frequencies of CD4+ naïve T cells and lower frequencies of CD16+ NK cells were also associated with clinical benefit to ICI therapy.Conclusions This study demonstrates that high-dimensional immune profiling can reveal novel blood-based immune signatures associated with risk and mechanism of severe irAEs. Development of severe irAEs in melanoma could be the result of reduced immune inhibitory capacity pre-ICI treatment, resulting in more activated TCM cells after treatment.https://jitc.bmj.com/content/12/1/e008056.full |
| spellingShingle | Siwen Hu-Lieskovan Ngan Nguyen Magdalena Kovacsovics-Bankowski John Hyngstrom Li-Chun Cheng Jordan P McPherson Umang Swami Matthew H Spitzer Johanna M Sweere Connor P Healy Natalia Sigal William D Chronister Shane A Evans John Marsiglio Berit Gibson Alyssa Erickson-Wayman Yoko S Derose Annaleah Larson Eliason Carlos O Medina Ramji Srinivasan Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma Journal for ImmunoTherapy of Cancer |
| title | Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma |
| title_full | Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma |
| title_fullStr | Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma |
| title_full_unstemmed | Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma |
| title_short | Lower frequencies of circulating suppressive regulatory T cells and higher frequencies of CD4+ naïve T cells at baseline are associated with severe immune-related adverse events in immune checkpoint inhibitor-treated melanoma |
| title_sort | lower frequencies of circulating suppressive regulatory t cells and higher frequencies of cd4 naive t cells at baseline are associated with severe immune related adverse events in immune checkpoint inhibitor treated melanoma |
| url | https://jitc.bmj.com/content/12/1/e008056.full |
| work_keys_str_mv | AT siwenhulieskovan lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT ngannguyen lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT magdalenakovacsovicsbankowski lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT johnhyngstrom lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT lichuncheng lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT jordanpmcpherson lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT umangswami lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT matthewhspitzer lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT johannamsweere lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT connorphealy lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT nataliasigal lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT williamdchronister lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT shaneaevans lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT johnmarsiglio lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT beritgibson lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT alyssaericksonwayman lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT yokosderose lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT annaleahlarsoneliason lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT carlosomedina lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma AT ramjisrinivasan lowerfrequenciesofcirculatingsuppressiveregulatorytcellsandhigherfrequenciesofcd4naivetcellsatbaselineareassociatedwithsevereimmunerelatedadverseeventsinimmunecheckpointinhibitortreatedmelanoma |