Interferon-Gamma-Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis.
| Title: | Interferon-Gamma-Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis. |
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| Authors: | Sasson SC; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Slevin SM; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Cheung VTF; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Nassiri I; Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.; Olsson-Brown A; Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; The Clatterbridge Cancer Centre National Health Service Foundation Trust, Wirral, United Kingdom.; Fryer E; Department of Cellular Pathology, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Ferreira RC; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.; Trzupek D; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.; Gupta T; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.; Al-Hillawi L; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Issaias ML; Department of Oncology, University of Oxford and Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.; Easton A; Department of Cellular Pathology, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Campo L; Translational Histopathology Laboratory, Department of Oncology, University of Oxford, United Kingdom.; FitzPatrick MEB; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Adams J; Berkshire Cancer Centre, Royal Berkshire Hospital, Reading, United Kingdom.; Chitnis M; Department of Oncology, University of Oxford and Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.; Protheroe A; Department of Oncology, University of Oxford and Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.; Tuthill M; Department of Oncology, University of Oxford and Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.; Coupe N; Department of Oncology, University of Oxford and Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.; Simmons A; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom.; Payne M; Department of Oncology, University of Oxford and Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.; Middleton MR; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom; Department of Oncology, University of Oxford and Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.; Travis SPL; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Fairfax BP; Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; Department of Oncology, University of Oxford and Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom.; Klenerman P; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.; Brain O; Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom. Electronic address: oliver.brain@ouh.nhs.uk. |
| Corporate Authors: | Oxford Inflammatory Bowel Disease Cohort Investigators |
| Source: | Gastroenterology [Gastroenterology] 2021 Oct; Vol. 161 (4), pp. 1229-1244.e9. Date of Electronic Publication: 2021 Jun 17. |
| Publication Type: | Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: W.B. Saunders Country of Publication: United States NLM ID: 0374630 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0012 (Electronic) Linking ISSN: 00165085 NLM ISO Abbreviation: Gastroenterology Subsets: MEDLINE |
| Imprint Name(s): | Publication: Philadelphia, PA : W.B. Saunders; Original Publication: Baltimore. |
| MeSH Terms: | CD8-Positive T-Lymphocytes/*drug effects ; Colitis/*chemically induced ; Colon/*drug effects ; Immune Checkpoint Inhibitors/*adverse effects ; Immunologic Memory/*drug effects ; Interferon-gamma/*metabolism ; Memory T Cells/*drug effects; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; CTLA-4 Antigen/antagonists & inhibitors ; CTLA-4 Antigen/metabolism ; Colitis/drug therapy ; Colitis/immunology ; Colitis/metabolism ; Colitis, Ulcerative/immunology ; Colitis, Ulcerative/metabolism ; Colon/immunology ; Colon/metabolism ; Lymphocyte Activation/drug effects ; Memory T Cells/immunology ; Memory T Cells/metabolism ; Piperidines/therapeutic use ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/metabolism ; Pyrimidines/therapeutic use ; Case-Control Studies ; Cross-Sectional Studies ; Gene Expression Profiling ; Humans ; Longitudinal Studies ; Phenotype ; Prospective Studies ; RNA-Seq ; Single-Cell Analysis ; Transcriptome |
| Abstract: | Background & Aims: The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets.; Methods: We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing.; Results: We demonstrate CD8+ tissue resident memory T (TRM) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8+ TRM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8+ TRM cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti-CTLA-4/PD-1 combination therapy and in anti-PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib.; Conclusions: Interferon gamma-producing CD8+ TRM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.; (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.) |
| Comments: | Comment in: Gastroenterology. 2021 Oct;161(4):1106-1108. doi: 10.1053/j.gastro.2021.07.007.. (PMID: 34256056) |
| References: | Nat Immunol. 2017 Aug;18(8):940-950. (PMID: 28628092); N Engl J Med. 2020 Jun 11;382(24):2374-2375. (PMID: 32521140); Immunity. 1994 Sep;1(6):447-56. (PMID: 7895156); J Clin Oncol. 2018 Jun 10;36(17):1714-1768. (PMID: 29442540); Clin Exp Immunol. 2020 Dec;202(3):335-352. (PMID: 32734627); JAMA Oncol. 2018 Dec 1;4(12):1721-1728. (PMID: 30242316); Sci Transl Med. 2020 Oct 14;12(565):. (PMID: 33055240); Nature. 2019 Jan;565(7739):366-371. (PMID: 30598548); Bioinformatics. 2017 Apr 15;33(8):1179-1186. (PMID: 28088763); Cell. 2019 Jun 13;177(7):1888-1902.e21. (PMID: 31178118); Nat Methods. 2015 Feb;12(2):115-21. (PMID: 25633503); Cancer Invest. 2017 Aug 9;35(7):443-455. (PMID: 28548891); Br J Cancer. 2020 Jul;123(2):207-215. (PMID: 32418993); Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7556-61. (PMID: 9636188); J Immunother Cancer. 2019 Apr 2;7(1):93. (PMID: 30940209); Cancer Cell. 2020 Oct 12;38(4):500-515.e3. (PMID: 32916126); Cell. 2018 Nov 1;175(4):998-1013.e20. (PMID: 30388456); Oncoimmunology. 2016 Jul 15;5(9):e1209615. (PMID: 27757302); Nat Med. 2018 Jul;24(7):986-993. (PMID: 29942092); Immunity. 2017 Feb 21;46(2):287-300. (PMID: 28214226); BMC Bioinformatics. 2018 Feb 20;19(1):56. (PMID: 29458351); Gastroenterology. 2021 Feb;160(3):932-934.e3. (PMID: 33096100); J Exp Med. 2019 Sep 2;216(9):2128-2149. (PMID: 31227543); Ann Rheum Dis. 2020 Nov;79(11):1400-1413. (PMID: 32759265); Nat Methods. 2017 Nov;14(11):1083-1086. (PMID: 28991892); JCI Insight. 2016 Dec 22;1(21):e88955. (PMID: 28018970); Cell. 2014 Nov 6;159(4):814-28. (PMID: 25417158); Nat Med. 2018 Dec;24(12):1804-1808. (PMID: 30420754); Nature. 2017 Jul 27;547(7664):413-418. (PMID: 28723893); Cell Syst. 2015 Dec 23;1(6):417-425. (PMID: 26771021); Gut. 2018 Nov;67(11):2056-2067. (PMID: 30131322); PLoS Comput Biol. 2017 Nov 3;13(11):e1005752. (PMID: 29099853); F1000Res. 2016 Aug 31;5:2122. (PMID: 27909575); Nucleic Acids Res. 2019 Jan 8;47(D1):D529-D541. (PMID: 30476227); Blood. 2018 May 24;131(21):e1-e11. (PMID: 29588278); N Engl J Med. 2015 Sep 24;373(13):1270-1. (PMID: 26398076); Genome Med. 2020 Jun 24;12(1):55. (PMID: 32580776); Genome Biol. 2016 Apr 27;17:75. (PMID: 27122128); Nat Commun. 2016 Aug 08;7:12335. (PMID: 27498556); Nat Biotechnol. 2018 Jan;36(1):89-94. (PMID: 29227470); Sci Immunol. 2017 Apr 14;2(10):. (PMID: 28738020); Cell Mol Immunol. 2020 Feb;17(2):113-122. (PMID: 31969685); Cell. 2020 Aug 6;182(3):655-671.e22. (PMID: 32603654); Clin Cancer Res. 2018 Jul 1;24(13):3036-3045. (PMID: 29599411); Cell. 2016 Oct 6;167(2):397-404.e9. (PMID: 27667683); N Engl J Med. 2016 Sep 1;375(9):819-29. (PMID: 27433843) |
| Grant Information: | MC_PC_MR/S025952/1 United Kingdom MRC_ Medical Research Council; U19 AI082630 United States AI NIAID NIH HHS; 201488/Z/16/Z United Kingdom WT_ Wellcome Trust; 107212/A/15/Z United Kingdom WT_ Wellcome Trust; MR/S036377/1 United Kingdom MRC_ Medical Research Council; MC_UU_00008/7 United Kingdom MRC_ Medical Research Council; MC_UU_12010/7 United Kingdom MRC_ Medical Research Council |
| Contributed Indexing: | Keywords: Checkpoint Colitis; Immunotherapy Colitis; Tofacitinib; Ulcerative Colitis |
| Substance Nomenclature: | 0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (IFNG protein, human); 0 (Immune Checkpoint Inhibitors); 0 (PDCD1 protein, human); 0 (Piperidines); 0 (Programmed Cell Death 1 Receptor); 0 (Pyrimidines); 82115-62-6 (Interferon-gamma); 87LA6FU830 (tofacitinib) |
| Entry Date(s): | Date Created: 20210620 Date Completed: 20220117 Latest Revision: 20250530 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC8527886 |
| DOI: | 10.1053/j.gastro.2021.06.025 |
| PMID: | 34147519 |
| Database: | MEDLINE |
Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't