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.

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). 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.

Interferon-Gamma–Producing CD8+ Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor–Colitis

“…We previously demonstrated that the majority of T cells in the colon of ICI-colitis were CD8 þ . 10 We sought to determine whether these CD8 þ T cells had a T RM cell phenotype. We found that both UC and DCC groups are associated with increased proportions of CD3 þ T cells in the affected tissue compared with healthy gut and DCNC groups, respectively (Figure 2Ai).…”

“…The available data suggested that anti-CTLA-4-associated colitis is associated with CD8 þ T cells 8 and an up-regulation of Th1 and Th17 effector pathways, including interferongamma (IFNG). 9 We previously demonstrated that anti-CTLA-4/PD-1 colitis is associated with high levels of activated (HLA-DR þ CD38 þ ) memory CD8 þ T cells, 10 and lower proportions of regulatory T cells compared with UC. 10 We hypothesized that CD8 þ T RM cells are implicated in the pathogenesis of ICI-colitis, postulating that they would become activated in an off-target consequence, and sought to understand the signaling pathways involved (Figure 1).…”

Single cell transcriptional profiling reveals helper, effector, and regulatory MAIT cell populations enriched during homeostasis and activation

“…At the protein level, these exhaustion markers were significantly upregulated in the 5-OP-RU condition, suggesting that chronic antigen-specific activation strongly induces negative feedback mechanisms to suppress further activation and proliferation. Taken together, these data imply that checkpoint blockade may enhance MAIT cell activity against infectious or malignant disease (Boulouis et al, 2020;Leeansyah et al, 2015;Venken et al, 2018) or contribute to autoimmune complications of immunotherapy (Sasson et al, 2020).…”

“…The copyright holder for this preprint this version posted October 24, 2020. ; https://doi.org/10.1101/2020.10.22.351262 doi: bioRxiv preprint Leeansyah et al, 2015;Venken et al, 2018) or contribute to autoimmune complications of immunotherapy (Sasson et al, 2020).…”

Systematic review: disease activity indices for immune checkpoint inhibitor‐associated enterocolitis

“…These indices include the MES, 17,27,[30][31][32][33] the van der Heide Score, 27,34 the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), 31,35,36 and the Simple Endoscopic Score for Crohn's Disease (SES-CD). 35 Notably, several of the endoscopic features identified in this review are component items of IBD indices.…”