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Clinical Trial
. 2019 Sep;46(9):627-636.
doi: 10.1111/cup.13454. Epub 2019 Apr 11.

Gene expression profiling of lichenoid dermatitis immune-related adverse event from immune checkpoint inhibitors reveals increased CD14+ and CD16+ monocytes driving an innate immune response

Jonathan L Curry  1   2   3 , Alexandre Reuben  4 , Robert Szczepaniak-Sloane  5 , Jing Ning  6 , Denái R Milton  6 , Chi H Lee  6 , Courtney Hudgens  3 , Saira George  2 , Carlos Torres-Cabala  1   2 , Daniel Johnson  7 , Sandesh Subramanya  3 , Jennifer A Wargo  5 , Kumaran Mudaliar  8 , Ignacio I Wistuba  3 , Victor G Prieto  1   2 , Adi Diab  7 , Michael T Tetzlaff  1   3
Affiliations
Clinical Trial

Gene expression profiling of lichenoid dermatitis immune-related adverse event from immune checkpoint inhibitors reveals increased CD14+ and CD16+ monocytes driving an innate immune response

Jonathan L Curry et al. J Cutan Pathol. 2019 Sep.

Abstract

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.

Keywords: CD14+ and CD16+ monocytes; checkpoint inhibitor; gene expression; immune-related adverse events; lichenoid dermatitis.

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