LAUSR

AIMS Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies by boosting immune-mediated destruction of neoplastic cells, but course with side effects stemming from generalized immune system activation against normal tissues. Checkpoint ligand expression in non-tumoral cells of tissues affected by immune-related adverse effects has been described in ICI-associated hypophysitis, myocarditis, and acute interstitial nephritis. We aimed to investigate the tissue expression of the immune checkpoint receptor PD-1 and its ligand, PD-L1, in PD-1 inhibitor-associated colitis. METHODS AND RESULTS PD-1 and PD-L1 immunohistochemical expression was analyzed in 15 cases of PD-1 inhibitor-associated colitis and potential mimics - infectious colitis and inflammatory bowel disease (IBD). Increased epithelial expression of PD-L1 was observed in PD1i-colitis when compared to normal colon and infectious colitis, but that was lower than expression in IBD. Conversely, PD-1 expression in inflammatory cells was higher in infectious colitis, intermediate in IBD and minimal or absent in normal colon and in patients receiving PD-1 inhibitors. CONCLUSIONS Although our results do not allow the use of PD-L1 as a discriminatory marker of PD1i-colitis against other entities within the differential diagnosis, they support the concept that ICI-colitis and IBD share similar pathogenetic mechanisms. They also highlight that PD-L1 epithelial overexpression is a commonly used mechanism of the gastrointestinal tract mucosa to protect itself from inflammatory-mediated damage from different etiologies, which likely underpins the high incidence of gastrointestinal IRAEs in patients receiving ICI therapies in which such mechanism is disrupted.