Thursday, October 24th, 9pm EST
Article discussed: 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
Authors:Curry JL, Reuben A, Szczepaniak-Sloane R, Ning J, Milton DR, Lee CH, Hudgens C, George S, Torres-Cabala C, Johnson D, Subramanya S, Wargo JA, Mudaliar K, Wistuba II, Prieto VG, Diab A, Tetzlaff MT
Temporary open access courtesy of Journal of Cutaneous Pathology at: https://onlinelibrary.wiley.com/doi/full/10.1111/cup.13454
Summary prepared by: Abdullah Alswied, MBBS, MRes, PhD (@AlswiedPath)
Journal club summary:
Background: Patients receiving checkpoint inhibitors (CPIs) may develop a number of immune‐related adverse events (irAEs), of which lichenoid dermatitis (LD) is the most common. The mechanism underlying the emergence of these irAEs remains poorly understood. The current study aims to determine the unique gene expression profiles and immune composition in LD—irAE.
Gene expression profiling on a series of LD—irAE (n = 3) and compared them with a series of sporadically occurring benign lichenoid keratosis (BLK) (n = 3). Profiled with NanoString nCounter PanCancer Immune Profiling Panel interrogating the mRNA levels of 770 genes. IHC analysis was performed. Benign lichenoid keratosis and Lichenoid dermatitis (immune-related adverse event) show indistinguishable histologic features.
Results and discussion:
LD—irAE exhibit upregulation of CD14 mRNA transcripts and TLR as compared with BLK control
Lichenoid dermatitis 2/2 immune-related adverse event exhibits upregulation of CD14 mRNA (a marker of monocyte and co-receptor for TLRs), higher numbers of CD14+ and CD16+ monocytes, downregulation of CD83 (a marker of mature dendritic cells), upregulation of chemotactic molecules, CXCL12 and CCL14.
Representative immunohistochemic stains for CD14, CD16, T‐Bet, Gata‐3, and FoxP3 in benign lichenoid keratosis (BLK) control (left) and LD—irAE (right)
TLRs – Toll like receptors are important mediators of the innate immune system response. Gene profiling of lichenoid dermatitis 2/2 immune-related adverse event bx showed upregulation of TLRs, CD14/TLR signaling pathway and MAPK.
LD—irAE exhibits a Th1 immune profile
The rationale for the statement above is the following:
T‐Bet is a known driver of pro-inflammatory responses (Th1), while GATA-3 is a known driver of anti-inflammatory responses (Th2) and FoxP3 (forkhead box P3) is a known T regulatory cells marker (Treg).
- LD-irAE exhibited lower Th2 expression as compared with BLK
- LD-irAE exhibited higher Th1 expression than Th2 expression overall
- LD-irAED exhibited lower FoxP3 expression as compared to BLK
- There is activation of the innate immune response through CD14/TLR signaling pathway in LD—irAE.
- LD—irAE may be related to checkpoint inhibitor therapy effect on CD14/TLR signaling of CD14+CD16+ monocytes recruited to the skin.
- Additional immune pathways involved in the development of LD—irAE include activation from skin microbiome, cytokines, and recruitment of CD14+CD16+ monocytes possibly initiate an inflammatory reaction that results in LD (summarized in the diagram below)
Some Highlights from the Evening:
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