TY - JOUR
T1 - Gene expression profiling and multiplex immunofluorescence analysis of bullous pemphigoid immune-related adverse event reveal upregulation of toll-like receptor 4/complement-induced innate immune response and increased density of TH1 T-cells
AU - Marques-Piubelli, Mario L.
AU - Seervai, Riyad N.H.
AU - Mudaliar, Kumaran M.
AU - Ma, Wencai
AU - Milton, Denái R.
AU - Wang, Jing
AU - Muhlbauer, Aaron
AU - Parra, Edwin R.
AU - Solis, Luisa M.
AU - Nagarajan, Priyadharsini
AU - Speiser, Jodi
AU - Hudgens, Courtney
AU - Cho, Woo Cheal
AU - Aung, Phyu P.
AU - Patel, Anisha
AU - Pacha, Omar
AU - Nelson, Kelly C.
AU - Tetzlaff, Michael T.
AU - Amaria, Rodabe N.
AU - Torres-Cabala, Carlos A.
AU - Prieto, Victor G.
AU - Wistuba, Ignacio I.
AU - Curry, Jonathan L.
N1 - Publisher Copyright:
© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2023/7
Y1 - 2023/7
N2 - Background: Immune checkpoint inhibitor (ICI)-based cancer therapies cause a variety of cutaneous immune-related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP-irAE remains a critical knowledge gap in the field of oncodermatology/oncodermatopathology. Methods: BP-irAE (n = 8) and de novo BP control (n = 8) biopsy samples were subjected to gene expression profiling using the NanoString® Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T-cells (CD3 and CD8), T helper 1 (TH1) cells (Tbet), TH2 cells (Gata3), TH17 cells (RORγT), and regulatory T-cells (Tregs; FoxP3) were further evaluated using InForm® image analysis. Results: Compared with de novo BP controls, BP-irAE samples exhibited upregulation of 30 mRNA transcripts (p < 0.025), including toll-like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (p < 0.025), including genes associated with TH2, TH17, and B-cell immune response. BP-irAE demonstrated a greater density of Tbet+ (TH1) cells in the dermis (p = 0.004) and fewer Tregs in the blister floor (p = 0.028) when compared with that of de novo control BP samples. Conclusions: BP-irAE exhibited activation of the TLR4/complement-driven classical innate immune response pathway, with dermal TH1 immune cell polarization and decreased Tregs in the blister floor. TLR/complement signaling may underlie the immunopathogenesis of BP-irAE.
AB - Background: Immune checkpoint inhibitor (ICI)-based cancer therapies cause a variety of cutaneous immune-related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP-irAE remains a critical knowledge gap in the field of oncodermatology/oncodermatopathology. Methods: BP-irAE (n = 8) and de novo BP control (n = 8) biopsy samples were subjected to gene expression profiling using the NanoString® Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T-cells (CD3 and CD8), T helper 1 (TH1) cells (Tbet), TH2 cells (Gata3), TH17 cells (RORγT), and regulatory T-cells (Tregs; FoxP3) were further evaluated using InForm® image analysis. Results: Compared with de novo BP controls, BP-irAE samples exhibited upregulation of 30 mRNA transcripts (p < 0.025), including toll-like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (p < 0.025), including genes associated with TH2, TH17, and B-cell immune response. BP-irAE demonstrated a greater density of Tbet+ (TH1) cells in the dermis (p = 0.004) and fewer Tregs in the blister floor (p = 0.028) when compared with that of de novo control BP samples. Conclusions: BP-irAE exhibited activation of the TLR4/complement-driven classical innate immune response pathway, with dermal TH1 immune cell polarization and decreased Tregs in the blister floor. TLR/complement signaling may underlie the immunopathogenesis of BP-irAE.
KW - bullous pemphigoid-irAE
KW - gene expression profiling
KW - immune mechanisms
KW - multiplex immunofluorescence
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U2 - 10.1111/cup.14442
DO - 10.1111/cup.14442
M3 - Article
C2 - 37150813
AN - SCOPUS:85158076549
SN - 0303-6987
VL - 50
SP - 661
EP - 673
JO - Journal of cutaneous pathology
JF - Journal of cutaneous pathology
IS - 7
ER -