Adaptive and Auto-Immunity| Volume 139, ISSUE 5, SUPPLEMENT , S6, May 2019

034 Skin rash secondary to checkpoint inhibitor immunotherapy is associated with a dense T cell and dendritic cell infiltrate and greater cellular proliferation in the dermis

      Checkpoint inhibitor immunotherapy is associated with a wide range of immune related adverse events (irAEs). Of these, skin rash is often the first to appear and severity may determine if therapy is interrupted or even withdrawn. In contrast, rash development has also been associated with improved survival. However, the mechanism underpinning rash development during immunotherapy remains unknown. Thus, we examined the makeup of immunotherapy-associated skin rash infiltrates with the goal of uncovering mechanistic insights behind rash development. Immunohistochemisty was used to describe the immune infiltrate in skin biopsies from healthy subjects and from a lesional site of patients with rash. Rash samples were obtained from 7 patients receiving α-PD1, α-CTLA4/α-PD1 combination or α-PDL1/α-NKG2A combination. Acetone-fixed sections from frozen biopsies were stained for CD3, CD8, CD68, CD11c, CD1a, CD207, or Ki67. Cell abundance in the dermis was compared among groups. Rash samples showed significant enrichment of T cells (CD3 p=0.01), CD8 T cells (p=0.03) and dendritic cells (CD11c p=0.03) in the dermis vs controls. More moderate enrichment of macrophages (CD68) was observed in rash versus control samples and dermal Langerhans cells (CD1a or CD207) showed equal abundance among groups. Finally, we observed a higher cellular proliferation in the dermis of rash vs control samples (Ki67 p=0.024), associated with areas of dense immune infiltration. Ki67 expression was highly correlated with both CD68 (r=0.89; p=0.012) and CD11c (r=0.786; p=0.048), suggesting myeloid cell proliferation. In conclusion, immunotherapy-associated skin rash contains an immune infiltrate dominated by T cells, CD8 T cells and dendritic cells, with increased cellular proliferation at sites of immune infiltration. These data strongly suggest skin rash may involve mechanisms beyond T cell activation.