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Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis.
  • +17
  • Sarah Sasson,
  • John Zaunders,
  • Kazi Nahar,
  • Cynthia Munier,
  • Benjamin Fairfax,
  • Anna Olsson-Brown,
  • Carol Jolly,
  • Scott Read,
  • Golo Ahlenstiel,
  • Umaimainthan Palendira,
  • Richard Scolyer,
  • Matteo Carlino,
  • Miranda Payne,
  • Vincent Cheung,
  • Tarun Gupta,
  • P Klenerman,
  • Georgina Long,
  • Oliver Brain,
  • Alex Menzies,
  • Anthony Kelleher
Sarah Sasson
University of Oxford
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John Zaunders
St Vincents Hospital Sydney
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Kazi Nahar
Melanoma Institute Australia
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Cynthia Munier
University of New South Wales
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Benjamin Fairfax
Oxford University Hospitals NHS Trust
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Anna Olsson-Brown
Royal Liverpool University Hospital
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Carol Jolly
Royal Liverpool University Hospital
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Scott Read
Westmead Millennium Institute for Medical Research
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Golo Ahlenstiel
Westmead Millennium Institute for Medical Research
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Umaimainthan Palendira
The University of Sydney
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Richard Scolyer
Melanoma Institute Australia
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Matteo Carlino
Melanoma Institute Australia
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Miranda Payne
Oxford University Hospitals NHS Trust
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Vincent Cheung
University of Oxford
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Tarun Gupta
University of Oxford
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P Klenerman
John Radcliffe Hospital
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Georgina Long
Melanoma Institute Australia
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Oliver Brain
University of Oxford
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Alex Menzies
Melanoma Institute Australia
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Anthony Kelleher
University of New South Wales
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Abstract

The aim of this study was to investigate the pathogenesis of combination ipilimumab and nivolumab-associated colitis (IN-COL) by measuring gut-derived and peripheral blood mononuclear cell (GMNC; PBMC) profiles. We studied GMNC and PBMC from patients with IN-COL, IN-treated with no adverse-events (IN-NAE), ulcerative colitis (UC) and healthy volunteers by flow cytometry. In the gastrointestinal-derived cells we found high levels of activated CD8+ T cells and mucosal-associated invariant T (MAIT) cells in IN-COL, changes that were not evident in IN-NAE or UC. UC but not IN-C was associated with a high proportion of regulatory T cells (Treg). We sought to determine if local tissue responses could be measured in peripheral blood. Peripherally, checkpoint-inhibition instigated a rise in activated memory CD4+ and CD8+ T cells, regardless of colitis. Low circulating MAIT cells at baseline was associated with IN-COL patients, compared with IN-NAE in one of two cohorts. UC but not IN-COL was associated with high levels of circulating plasmablasts. In summary, the alterations in T cell subsets measured in IN-COL-affected tissue, characterised by high levels of activated CD8+ T cells and MAIT cells and a low proportion of Treg, reflected a pathology distinct from UC. These tissue changes differed from the periphery, where T cell activation was a widespread on-treatment effect, and circulating MAIT cell count was low but not reliably predictive of colitis (Figure1).

Peer review status:ACCEPTED

16 Mar 2020Submitted to Clinical & Experimental Immunology
16 Mar 2020Submission Checks Completed
16 Mar 2020Assigned to Editor
24 Mar 2020Reviewer(s) Assigned
05 Apr 2020Review(s) Completed, Editorial Evaluation Pending
13 Apr 2020Editorial Decision: Revise Major
09 Jun 20201st Revision Received
10 Jun 2020Reviewer(s) Assigned
26 Jun 2020Review(s) Completed, Editorial Evaluation Pending
07 Jul 2020Editorial Decision: Accept