Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor colitis.

Colitis is a prevalent adverse event associated with immune checkpoint inhibitor (ICI) therapy with similarities to inflammatory bowel disease. Incomplete mechanistic understanding of ICI colitis curtails evidence-based treatment. Given the often-overlooked connection between tissue architecture and mucosal immune cell function, we here applied imaging mass cytometry (IMC) to gain spatial proteomic insight in ICI colitis in comparison to ulcerative colitis (UC). Using a cell segmentation pipeline that simultaneously utilizes high-resolution nuclear imaging and high-multiplexity IMC, we show that intra-epithelial CD8 ⁺ T cells are significantly more abundant (and numerically dominant) in anti-PD-1 ± anti-CTLA-4-induced colitis compared to anti-CTLA-4-induced colitis and UC. We identified activated, cycling CD8 ⁺ tissue-resident memory T _(RM) cells at the lamina propria-epithelial interface as drivers of cytotoxicity in ICI colitis and UC. Moreover, we found that combined ICI-induced colitis featured highest granzyme B levels both in tissue and serum. Together, these data reinforce CD8 ⁺ T _RM cells as potentially targetable drivers of ICI colitis.
Competing Interests: E.B. received research funding from Pfizer and is supported by the Alexandre Suerman stipend for MD/PhD candidates of the UMC Utrecht. Y.V. has received speaker fees from Johnson & Johnson, research funding from Galapagos, and a Public Private Partnership grant from Health Holland (#TKI2017), with TigaTx B.V. K.S. has advisory relationships with Bristol Myers Squibb, Novartis, MSD, Pierre Fabre, and AbbVie, and received honoraria from Novartis, MSD, and Roche and research funding from BMS, Philips, and TigaTx. All paid to institution. F.W. has received advisory/speaker fees from Takeda and Johnson & Johnson and research funding from BMS, Takeda, Sanofi, Pfizer, Galapagos, and Leo Pharma.
(© 2023 The Author(s).)