Histologic and Immune Characterization of Cutaneous Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors

Authors

Omar Pacha
Anisha B Patel
Jonathan L Curry
Cara L Haymaker
Nejla Ozirmak Lermi
Dzifa Yawa Duose
Ken Chen
Joud Hajjar
Aung Naing

Publication Date

8-7-2025

Journal

The Journal for ImmunoTherapy of Cancer

DOI

10.1136/jitc-2024-011401

PMID

40780859

PMCID

PMC12336593

PubMedCentral® Posted Date

8-7-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Although immune checkpoint inhibitors (ICIs) are efficacious, they often cause immune-related adverse events (irAEs), most commonly cutaneous irAEs (CirAEs). The mechanisms underlying CirAEs remain unclear.

Methods: Attempting to better understand their mechanisms and histology we conducted a prospective study of 15 patients with advanced cancers treated with ICIs who developed grade 2 or higher CirAEs. Clinical and histologic characterization of biopsy specimens of CirAEs was performed. Histologic analysis of patient biopsy specimens were subdivided by epidermal reaction patterns that included spongiotic, lichenoid, and interface dermatitis patterns. A targeted RNA expression assay was used to identify immune markers in CirAE lesions and adjacent unaffected skin samples.

Conclusions: Compared with adjacent unaffected skin, CirAE lesions had significantly upregulated THY1 (CD90) and increased M2 macrophages (adjusted p< 0.05). Our findings suggest that CirAEs exhibit diverse histologic patterns that may mimic autoimmune skin diseases. The lack of distinct biomarker signatures may indicate complex and heterogeneous mechanisms underlying CirAEs; however, the upregulation of THY1 and elevated numbers of M2 macrophages in CirAE lesions suggest THY1 and M2 macrophages may be involved in the pathogenesis of these toxic effects. Further investigation to elucidate the molecular determinants of CirAEs and develop targeted therapeutic strategies is warranted.

Keywords

Humans, Immune Checkpoint Inhibitors, Male, Female, Aged, Middle Aged, Prospective Studies, Skin Diseases, Neoplasms, Aged, 80 and over, Dermatitis, Histology, Immunotherapy, Rash

Published Open-Access

yes

Recommended Citation

Pacha, Omar; Patel, Anisha B; Curry, Jonathan L; et al., "Histologic and Immune Characterization of Cutaneous Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors" (2025). Faculty, Staff and Student Publications. 4472.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4472