GSE210037
Checkpoint blockade-induced dermatitis and colitis are dominated by tissue resident memory T cells and  Th1/Tc1 cytokines
Immune checkpoint blockade (ICB) is therapeutically successful in multiple cancer types. However, immune-related adverse events (irAE) frequently occur and can sometimes be life-threatening. It is critical to understand the immunologic mechanisms of irAEs with the goal of finding novel treatment targets. Therefore, we studied tissues from irAE dermatitis cases using multiparameter immunofluorescence (IF), spatial transcriptomics, and RNA in situ hybridization. Skin psoriasis cases were studied as a comparison, as a known Th17-driven disease, and colitis was investigated as a comparison. IF analysis revealed that CD4+ and CD8+ tissue resident memory T (TRM) cells were preferentially expanded in the inflamed portion of skin in cutaneous irAEs compared to healthy skin controls. Spatial transcriptomics allowed focusing attention on areas containing TRM cells to discern their functional phenotype, and revealed expression of Th1-associated genes in irAE, compared to Th17-asociated genes in psoriasis. Expression of a range of inhibitory checkpoint molecules was observed, including PD-1, CTLA-4, LAG-3, and TIGIT. RNA in situ hybridization (RISH) technology combined with IF confirmed expression of IFN-?, CXCL9, CXCL10, and TNF-a in additional irAE dermatitis cases and allowed us to identify production of IFN-? within TRM cells specifically. The Th1-skewed phenotype was confirmed in irAE colitis cases compared to healthy colon. Overall design: spatial transcriptomics: skin irAE vs. Psoriasis, colon irAE vs. healthy colon