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

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 þ tissue resident memory T (T RM ) cells are the dominant activated T cell subset in ICIcolitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and Gastroenterology 2021;161:1229-1244 BASIC AND TRANSLATIONAL AT epithelial-signaling levels. CD8 þ T RM cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8 þ T RM 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 ICIcolitis, using the JAK inhibitor tofacitinib. CONCLUSIONS: Interferon gamma-producing CD8 þ T RM cells are a pathological hallmark of ICI-colitis and a novel target for therapy.

Distinct immune-effector and metabolic profile of CD8+ T Cells in patients with autoimmune polyarthritis induced by therapy with immune-checkpoint inhibitors

“…The identified effector CD8 meta-clusters were slightly more abundant in ICI-irAE, AA-CNT and AA-MAL than in ICI-CNT patients. This enrichment of effector/activated CD8 in ICI-irAE patients has been equally been reported in the peripheral blood of thymic epithelial tumor and metastatic NSCLC patients developing different forms of irAEs [26], in the epidermis of melanoma, renal cell carcinoma, gastric cancer and lung cancer patients with ICI-induced psoriasis-like dermatitis [27], and in the colon epithelium of melanoma patients with ICI-induced colitis [28]. Thus, they seem to help fuelling the (autoimmune) inflammatory response in ICI.…”

Unravelling Checkpoint Inhibitor Associated Autoimmune Diabetes: From Bench to Bedside

“…One example is ICI related colitis, which is amongst the best studied of the irAE due to accessibility of tissue for histopathology. Colonic biopsies from patients with ICI related colitis demonstrated high levels of activated CD8+ T cells and relatively lower proportions of Treg cells in comparison to ulcerative colitis affected patients, indicating distinct immunological differences between the two diseases and also highlighting a key pathogenic role for T cells in this disease (29,30). Contrastingly, histopathology from patients with ICI induced hypophysitis demonstrated both T and B cell infiltration with CTLA4 expression within pituitary cells and positive antipituitary antibodies in the circulation (31).…”

The Inhibitory Receptor GPR56 (Adgrg1) Is Specifically Expressed by Tissue-Resident Memory T Cells in Mice But Dispensable for Their Differentiation and Function In Vivo

“…We also did not find evidence that GPR56 contributed to the regulation of the cytolytic enzyme granzyme B in T RM cells, suggesting that the regulatory role of GPR56 is not essential under these conditions. Evidence is accumulating that expression of inhibitory receptors, such as PD-1, on T RM cells is highly relevant to protect against T RM cell-driven inflammatory responses that otherwise may develop in the intestine, pancreas, and the lungs [18][19][20]. Possibly, the inhibitory impact of GPR56 in the regulation of T RM cells is masked by the presence of other inhibitory receptors on T RM cells.…”

“…However, the long-term persistence of these proinflammatory memory T cells in peripheral tissues during the steady state also appears to require control mechanisms to prevent inadvertent immune activation. Indeed, T RM cells highly express inhibitory receptors such as PD-1, which protect the peripheral tissues against proinflammatory actions of T RM cells under homeostatic conditions [18][19][20].…”