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.,Clinical & Experimental Immunology

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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.
Clinical & Experimental Immunology ( IF 3.4 ) Pub Date : 2020-07-31 , DOI: 10.1111/cei.13502
S C Sasson ₁ , J J Zaunders ₂ , K Nahar ₃ , C M L Munier ₄ , B P Fairfax _{5,

6,

7} , A Olsson-Brown ₈ , C Jolly ₈ , S A Read _{9,

10} , G Ahlenstiel _{9,

11} , U Palendira ₁₂ , R A Scolyer _{3,

13} , M S Carlino _{3,

14} , M J Payne ₅ , V T F Cheung ₁ , T Gupta _{1,

7} , P Klenerman _{1,

15} , G V Long _{3,

16} , O Brain _{1,

17} , A M Menzies _{3,

16} , A D Kelleher _{2,

4}

Affiliation

Translational Gastroenterology Unit and Oxford Biomedical Research Centre, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia.
Melanoma Institute Australia and The University of Sydney, Sydney, Australia.
The Kirby Institute, University of New South Wales, Sydney, Australia.
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.
The Clatterbridge Cancer Centre NHS Foundation Trust and Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Westmead Institute of Medical Research, Sydney, Australia.
Western Sydney University, Sydney, Australia.
Department of Gastroenterology, Blacktown Hospital, Sydney, Australia.
Discipline of Infectious Diseases and Immunology, The University of Sydney, Sydney, Australia.
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, Australia.
Department of Medical Oncology, Westmead and Blacktown Hospitals, Sydney, Australia.
Peter Medawar Building of Pathogen Research, University of Oxford, Oxford, UK.
Department of Medical Oncology, Royal North Shore Hospital and Mater Hospitals, Sydney, Australia.
Department of Gastroenterology, John Radcliffe Hospital, Oxford, UK.

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 (T_reg). 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 T_reg, 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.

中文翻译：

黏膜相关不变 T (MAIT) 细胞在 ipilimumab 和 nivolumab 联合治疗相关结肠炎患者的胃肠道组织中被激活，其病理学不同于溃疡性结肠炎。

本研究的目的是通过测量肠源性和外周血单个核细胞 (GMNC; PBMC) 谱来研究 ipilimumab 和 nivolumab 相关结肠炎 (IN-COL) 联合用药的发病机制。我们使用流式细胞仪研究了 IN-COL、IN 治疗无不良事件 (IN-NAE)、溃疡性结肠炎 (UC) 和健康志愿者的 GMNC 和 PBMC。在胃肠道来源的细胞中，我们在 IN-COL 中发现了高水平的活化 CD8 ⁺ T 细胞和黏膜相关不变 T (MAIT) 细胞，这些变化在 IN-NAE 或 UC 中不明显。UC 而非 IN-C 与高比例的调节性 T 细胞（T _reg）。我们试图确定是否可以在外周血中测量局部组织反应。在外围，无论结肠炎如何，检查点抑制都会导致激活的记忆 CD4 ⁺和 CD8 ^{+ T 细胞增加。}在两个队列之一中，与 IN-NAE 相比，基线时低循环 MAIT 细胞与 IN-COL 患者相关。UC（而非 IN-COL）与高水平的循环浆母细胞相关。总之，在 IN-COL 影响的组织中测量的 T 细胞亚群的改变，其特征是高水平的活化 CD8 ⁺ T 细胞和 MAIT 细胞和低比例的 T _reg，反映了与 UC 不同的病理学。这些组织变化与外周不同，在外周，T 细胞活化是一种广泛的治疗效果，循环 MAIT 细胞计数低，但不能可靠地预测结肠炎。

更新日期：2020-07-31

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