Molecular analysis of immune checkpoint inhibitor associated erythema nodosum-like toxicity

Xiaopeng Sun; Margaret L Axelrod; Paula I Gonzalez-Ericsson; Violeta Sanchez; Yu Wang; Jonathan L Curry; Elizabeth J Phillips; Yaomin Xu; Douglas B Johnson; Justin M Balko

doi:10.3389/fimmu.2025.1542499

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Molecular analysis of immune checkpoint inhibitor associated erythema nodosum-like toxicity

Journal article

Open access

Peer reviewed

Molecular analysis of immune checkpoint inhibitor associated erythema nodosum-like toxicity

Xiaopeng Sun, Margaret L Axelrod, Paula I Gonzalez-Ericsson, Violeta Sanchez, Yu Wang, Jonathan L Curry, Elizabeth J Phillips, Yaomin Xu, Douglas B Johnson and Justin M Balko

Frontiers in immunology, Vol.16, 1542499

2025

DOI: https://doi.org/10.3389/fimmu.2025.1542499

PMID: 40181973

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Abstract

Brain Neoplasms - drug therapy

Brain Neoplasms - immunology

Brain Neoplasms - secondary

Erythema Nodosum - chemically induced

Erythema Nodosum - diagnosis

Erythema Nodosum - genetics

Erythema Nodosum - immunology

Female

Humans

Immune Checkpoint Inhibitors - adverse effects

Ipilimumab - adverse effects

Male

Melanoma - drug therapy

Melanoma - immunology

Melanoma - pathology

Middle Aged

Nivolumab - administration & dosage

Nivolumab - adverse effects

Receptors, Antigen, T-Cell - genetics

Purpose Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancy but can induce immune-related adverse events (irAE). The mechanisms behind these sporadic and sometimes life-threatening irAEs remain largely unexplored. Here, we present a case report and in-depth molecular analysis of an erythema nodosum (EN) like irAE occurring in a melanoma patient with isolated brain metastasis, aiming to explore the potential mechanism of this irAE. Methods We performed RNA and T cell receptor (TCR) sequencing on the patient’s resected brain metastasis and biopsy of EN-like irAE. Single cell RNA/TCR sequencing was conducted on the patient’s peripheral blood mononuclear cells (PBMC) at baseline, 3 weeks after ipilimumab and nivolumab combination therapy, during EN toxicity and after resolution. Results The site of EN-like irAE showed a distinct accumulation of pro-inflammatory immune cells, accompanied by the upregulation of inflammatory and interferon response signatures. In addition, clonal expansion and activation of irAE-associated CD8 T cells and upregulation of monocyte-specific interferon signatures occurred concurrently with irAE onset. Conclusion The unique immune landscape at the EN-like irAE could indicate that this irAE is distinct from anti-tumor immune and analogous non-ICI autoimmune milieus. Our data also suggests that systemic immune activation induced by ICI treatment, as reflected in PBMC, may help monitor the patient’s treatment response and access irAE risk.

Details

Title: Molecular analysis of immune checkpoint inhibitor associated erythema nodosum-like toxicity
Authors/Creators: Xiaopeng Sun - Vanderbilt University Medical Center
Margaret L Axelrod - Washington University in St. Louis
Paula I Gonzalez-Ericsson - Vanderbilt University Medical Center
Violeta Sanchez - Vanderbilt University Medical Center
Yu Wang - Vanderbilt University Medical Center
Jonathan L Curry - The University of Texas MD Anderson Cancer Center
Elizabeth J Phillips - Vanderbilt University Medical Center
Yaomin Xu - Vanderbilt University Medical Center
Douglas B Johnson - Vanderbilt University Medical Center
Justin M Balko - Vanderbilt University Medical Center
Publication Details: Frontiers in immunology, Vol.16, 1542499
Publisher: Frontiers Media
Identifiers: 991005884945607891
Murdoch Affiliation: Research and Innovation Office; Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Journal article

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