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Background: Cancer patients receiving antibodies abrogating immune checkpoint pathways may develop a diverse array of immune-related adverse events (irAEs), of which lichenoid dermatitis (LD) is the most common. The mechanism driving the emergence of these irAEs remain understudied, underscoring a critical need to determine the unique gene expression profiles and immune composition in LD-irAE., Methods: LD-irAE (n = 3) and benign lichenoid keratosis (BLK) control (n = 3) were profiled with NanoString nCounter PanCancer Immune Profiling Panel interrogating the mRNA levels of 770 genes. Immunohistochemical (IHC) studies (n = 14 samples) for CD14, CD16, T-Bet, Gata-3, and FoxP3 were further evaluated using Aperio digital image analysis., Results: The LD-irAE showed downregulation of 93 mRNA transcripts (P < 0.05) and upregulation of 74 mRNA transcripts (P < 0.04) including toll-like receptor (TLR) 2 and TLR4 (P < 0.05). CD14 + and CD16 + monocytes quantified by IHC (H-score) were higher in LD-irAE than in the BLK control (P < 0.05). The immune composition of LD-irAE exhibited higher numbers of T-Bet + (Th1) cells compared with Gata-3 + (Th2) cells (P = 0.016) and lower numbers of FoxP3 (T regulatory) cells (P = 0.008)., Conclusions: LD-irAE exhibited activation of CD14/TLR innate immune response with increased CD14 + and CD16 + monocytes compared with BLK control. CD14/TLR signaling may drive the development of LD-irAE., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)