Histologic and immune characterization of cutaneous immune-related adverse events induced by immune checkpoint inhibitors.

Background: Although immune checkpoint inhibitors (ICIs) are efficacious, they often cause immune-related adverse events (irAEs), most commonly cutaneous irAEs (CirAEs). The mechanisms underlying CirAEs remain unclear.

Methods: Attempting to better understand their mechanisms and histology we conducted a prospective study of 15 patients with advanced cancers treated with ICIs who developed grade 2 or higher CirAEs. Clinical and histologic characterization of biopsy specimens of CirAEs was performed. Histologic analysis of patient biopsy specimens were subdivided by epidermal reaction patterns that included spongiotic, lichenoid, and interface dermatitis patterns. A targeted RNA expression assay was used to identify immune markers in CirAE lesions and adjacent unaffected skin samples.

Conclusions: Compared with adjacent unaffected skin, CirAE lesions had significantly upregulated () and increased M2 macrophages (adjusted p<0.05). Our findings suggest that CirAEs exhibit diverse histologic patterns that may mimic autoimmune skin diseases. The lack of distinct biomarker signatures may indicate complex and heterogeneous mechanisms underlying CirAEs; however, the upregulation of and elevated numbers of M2 macrophages in CirAE lesions suggest and M2 macrophages may be involved in the pathogenesis of these toxic effects. Further investigation to elucidate the molecular determinants of CirAEs and develop targeted therapeutic strategies is warranted.