Summary:
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).