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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 |
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| Authors: | S. C. Sasson J. J. Zaunders K. Nahar C. M. L. Munier B. P. Fairfax A. Olsson-Brown C. Jolly S. A. Read G. Ahlenstiel U. Palendira R. A. Scolyer M. S. Carlino M. J. Payne V. T. F. Cheung T. Gupta P. Klenerman G. V. Long O. Brain A. M. Menzies A. D. Kelleher |
| Affiliation: | 1. Translational Gastroenterology Unit and Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK;2. Centre for Applied Medical Research, St Vincent’s Hospital, Sydney, Australia;3. Melanoma Institute Australia and The University of Sydney, Sydney, Australia;4. The Kirby Institute, University of New South Wales, Sydney, Australia;5. Department of Oncology, Churchill Hospital, Oxford, UK Department of Oncology, University of Oxford, Oxford, UK MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK;6. The Clatterbridge Cancer Centre NHS Foundation Trust and Institute of Translational Medicine, University of Liverpool, Liverpool, UK;7. Westmead Institute of Medical Research, Sydney, Australia Western Sydney University, Sydney, Australia;8. Westmead Institute of Medical Research, Sydney, Australia Department of Gastroenterology, Blacktown Hospital, Sydney, Australia;9. Discipline of Infectious Diseases and Immunology, The University of Sydney, Sydney, Australia;10. Melanoma Institute Australia and The University of Sydney, Sydney, Australia Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia;11. Melanoma Institute Australia and The University of Sydney, Sydney, Australia Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, Australia;12. Department of Oncology, Churchill Hospital, Oxford, UK;13. Translational Gastroenterology Unit and Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK;14. Translational Gastroenterology Unit and Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK Peter Medawar Building of Pathogen Research, University of Oxford, Oxford, UK;15. Melanoma Institute Australia and The University of Sydney, Sydney, Australia Department of Medical Oncology, Royal North Shore Hospital and Mater Hospitals, Sydney, Australia;16. Translational Gastroenterology Unit and Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK Department of Gastroenterology, John Radcliffe Hospital, Oxford, UK These authors supervised this work equally.;17. Melanoma Institute Australia and The University of Sydney, Sydney, Australia Department of Medical Oncology, Royal North Shore Hospital and Mater Hospitals, Sydney, Australia These authors supervised this work equally.;18. Centre for Applied Medical Research, St Vincent’s Hospital, Sydney, Australia The Kirby Institute, University of New South Wales, Sydney, Australia These authors supervised this work equally. |
| 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 using 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, characterized 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. |
| Keywords: | checkpoint inhibitor colitis ipilimumab MAIT cells nivolumab |