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. 2025 May 31;17(11):1845.
doi: 10.3390/cancers17111845.

Interleukin-4 and -13 Gene Expression Profiles in Immune-Related Bullous Pemphigoid Indicate Efficacy of IL-4/IL-13 Inhibitors

Lisa Arnold  1 , Monika Morak  1 , Nora Kramer  1 , Carola Berking  2 , Matthias Schefzyk  3 , Jessica C Hassel  4 , Mirjana Ziemer  5 , Lars E French  1   6 , Ralf Gutzmer  7 , Dorothee Nashan  8 , Lucie Heinzerling  1   2
Affiliations

Interleukin-4 and -13 Gene Expression Profiles in Immune-Related Bullous Pemphigoid Indicate Efficacy of IL-4/IL-13 Inhibitors

Lisa Arnold et al. Cancers (Basel). .

Abstract

Background/Objectives: Cutaneous side effects are the most common immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) and affect 70-90% of patients. Besides diverse types of exanthema, rare skin toxicity includes bullous dermatoses in 0.3% of cases. Systemic steroids are the first-line treatment for immune-related bullous pemphigoid (irBP); however, some cases are corticosteroid-resistant. IrBP is one of the irAEs most frequently chronic and associated with long-term steroid use. However, steroids may interfere with tumor response. Therefore, alternative treatment strategies for irBP are desperately needed. Dupilumab, a monoclonal antibody blocking the receptor binding of interleukin-4 (IL-4) and interleukin-13 (IL-13), has been successfully used to treat spontaneous forms of bullous pemphigoid (BP). In this study, we analyzed the gene expression profiles of BP and irBP. Patients and Methods: A retrospective multicenter study evaluated the gene expression profiles of irBP and BP in comparison to healthy controls. Gene expression analyses of skin biopsies were performed using NanoString technology from patients with BP (n = 17), irBP (n = 19), and healthy skin (n = 24) after the patients had consented to participate in this study, and differentially expressed genes (DEGs) were determined using Rosalind software. Results: Compared to healthy skin, BP showed 167 DEGs, and irBP revealed 99 DEGs. Some of the DEGs from irBP and BP vs. healthy skin overlapped. Specifically, IL-4- and IL-13-associated genes were upregulated in both irBP and BP compared to healthy skin. Interestingly, expression profiles of BP vs. irBP also showed 13 DEGs. Conclusions: These findings suggest a possibility for therapeutic efficacy of IL-4 and IL-13 inhibitors in the treatment of irBP.

Keywords: anti-PD1-antibody; autoimmunity; bullous pemphigoid; cutaneous side effects; gene expression; immune checkpoint inhibitor; immune-related adverse events; immune-related bullous pemphigoid; skin.

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Conflict of interest statement

L.H. has received speaker/consultancy fees from Amgen, BiomeDx, BMS, Curevac, Merck, MSD, Myoncare, Novartis, Pierre-Fabre, Roche, Sanofi and SUN. RG reports grants or contracts from Novartis, Sun Pharma, Amgen, Sanofi/Regeneron, Merck-Serono, Kyowa-Kirin, Recordati, and Almirall-Hermal; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Regeneron, and Merck-Serono; support for attending meetings and/or travel from Sun Pharma, Pierre Fabre; participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Delcath, Pierre Fabre, Merck-Serono, Sun Pharma, Merck-Serono, Sanofi, and Immunocore. M.Z. has received speaker/consultancy fees from BMS, MSD, Novartis, Pierre-Fabre, Sanofi and Sunpharma and financial support for congress participation from Sunpharma and Sanofi. CB reports payment or honoraria for lectures, presentations, or educational events from Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, and Regeneron; participation on a data safety monitoring board or advisory board for Delcath, InflaRx, Miltenyi, Bristol Myers Squibb, Novartis, Merck Sharp & Dohme, Almirall-Hermal, Pierre Fabre, Regeneron, Sanofi, and Immunocore. N.K. has received financial support for congress participation from Sun Pharma. M.S. received honoraria as speaker and for consultation from Almirall, AbbVie and Sanofi. J.C.H. has received honoraria from Amgen, BMS, Delcath, GSK, MSD, Novartis, Pierre Fabre, Roche, Sanofi, and Sunpharma; has served as a consultant or advisor for GSK, MSD, Pierre Fabre, Sunpharma, Immunocore, Nektar, Novartis, Philogen, Sanofi, BMS, Sunpharma, and Sanofi; and research funding or support for clinical studies from BMS, Sunpharma, Sanofi, AstraZeneca, BioNTech, BMS, Genentech/Roche, Genmab, Idera, Immunocore, IOBiotech, Iovance, Nektar, Novartis, Philogen, Pierre Fabre, Regeneron, Replimune, Sanofi, and Seagen. D.N. served as a consultant and paid referee for MSD, BMS, Novartis, Roche, Almirall Hermal, Mylan, and Sanofi, outside the submitted work. L.F. declares speakers’ and advisory board honoraria from Galderma, Janssen, Leo Pharma, Eli Lilly, Almirall, Union Therapeutics, Regeneron, Novartis, Amgen, Abbvie, UCB, Biotest, AC-Immune, Vaderis Therapeutics, InflaRx, and Alys Pharmaceuticals. All other authors state no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanism of action: dupilumab (green semicircle) specifically targets the interleukin-4 receptor alpha chain (IL-4Rα) on immune cell surfaces. IL-4 and IL-13 signaling requires dimerization of IL-4Rα with either the common gamma chain (IL-4Rγ, for IL-4 signaling) or the interleukin-13 receptor (IL-13Rα1, for IL-13 or IL-4 signaling). Lebrikizumab and tralokinumab (purple donuts) bind IL-13, thereby preventing its interaction with the IL-13 receptor (IL-13Rα1 and IL-13Rα2) and thus blocking the IL-13 signaling (created in https://BioRender.com).
Figure 2
Figure 2
(a) Volcano plot with 168 DEGs of 150 upregulated (green) and 18 downregulated (purple) genes obtained from the NanoString analysis comparing BP (n = 17) vs. healthy skin (n = 24). IL-13, IL-4, and IL-13 RA2, as highly significant upregulated DEGs, are marked. The black dots below the x-axis represent genes that are not significantly changed. (b) Multidimensional Scaling (MDS) plot of skin samples from BP patients (BP, green dots) and healthy skin (Healthy skin, orange dots) from healthy donors showing a grouping of the two different cohorts. BP: bullous pemphigoid.
Figure 3
Figure 3
(a) Volcano plot with 99 DEGs of 82 upregulated (green) and 17 downregulated (purple) genes obtained from the NanoString analysis comparing irBP (n = 19) vs. healthy skin (n = 24). IL-13, IL-4, and IL-13 RA2, as highly significantly upregulated DEGs, are marked. The black dots below the x-axis represent genes that are not significantly changed. (b) Multidimensional Scaling (MDS) plot of skin samples from irBP patients (irBP, orange dots) and healthy skin (Healthy skin, green dots) from healthy donors, showing a separation of the two different patient groups. irBP: immune-related bullous pemphigoid.
Figure 4
Figure 4
(a) Volcano plot with 13 DEGs of 4 upregulated (green) and 9 downregulated (purple) genes obtained from the NanoString analysis comparing BP (n = 17) vs. irBP (n = 19). The black dots below the x-axis represent genes that are not significantly changed. (b) The Multidimensional Scaling (MDS) plot of skin samples from BP patients (BP, green dots), and irBP patients (irBP, orange dots) does not distinguish between the two diseases. BP: bullous pemphigoid; irBP: immune-related bullous pemphigoid.
Figure 5
Figure 5
MDS plot showing irBP patients (grey circle; females: brown dots, males: grey dots), BP patients (purple circle; females: orange dots, males: purple dots), and healthy controls (green circle; females: green dots, males: yellow dots). A grouping is observable between the disease entities, but not between sexes. BP: bullous pemphigoid; irBP: immune-related bullous pemphigoid; HS: healthy skin; F: Female; M: Male.
Figure 6
Figure 6
Histopathologic findings of irBP in a patient treated with pembrolizumab. Subepidermal blister with a band-like mixed inflammatory infiltrate containing eosinophils in the dermis. Representative example of H&E staining. Microscope’s magnification x20.
Figure 7
Figure 7
Graphical representation of the IL-4/IL-13 signaling pathway, including the genes described in Table 1. IL-4 and IL-13 bind to their respective receptors, leading to the activation of the JAK3/JAK1/TYK2 signaling cascade and subsequent activation of STAT3/6. STAT6 then binds to the promoter region of CCL26, resulting in its increased transcription. An alternative signaling pathway involves the signaling molecules ERK1/2 (MAPK3/1), which contribute to cell growth, cytokine production, and tissue remodeling. Information on pathway components was obtained from the Reactome database (created using https://BioRender.com).
Figure 8
Figure 8
Graphical representation of the overlapping DEGs, proportional in size, between irBP vs. healthy donors and BP vs. healthy donors. A total of 66 overlapping DEGs were identified, which corresponds to approximately 65% of the DEGs from irBP vs. healthy donors and approximately 38% of the DEGs from BP vs. healthy donors. BP: bullous pemphigoid; irBP: immune-related bullous pemphigoid; DEG: differentially expressed genes.
See this image and copyright information in PMC

References

    1. Schulz T.U., Zierold S., Sachse M.M., Pesch G., Tomsitz D., Schilbach K., Kähler K.C., French L.E., Heinzerling L. Persistent immune-related adverse events after cessation of checkpoint inhibitor therapy: Prevalence and impact on patients’ health-related quality of life. Eur. J. Cancer. 2022;176:88–99. doi: 10.1016/j.ejca.2022.08.029. - DOI - PubMed
    1. Kuo A.M.S., Gu S., Stoll J., Moy A.P., Dusza S.W., Gordon A., Haliasos E.C., Janjigian Y., Kraehenbuehl L., Quigley E.A., et al. Management of immune-related cutaneous adverse events with dupilumab. J. Immunother. Cancer. 2023;11:e007324. doi: 10.1136/jitc-2023-007324. - DOI - PMC - PubMed
    1. Kawsar A., Edwards C., Patel P., Heywood R.M., Gupta A., Mann J., Harland C., Heelan K., Larkin J., Lorigan P., et al. Checkpoint inhibitor-associated bullous cutaneous immune-related adverse events: A multicentre observational study. Br. J. Dermatol. 2022;187:981–987. doi: 10.1111/bjd.21836. - DOI - PubMed
    1. Kramer N., Müller G., Zierold S., Röckel M., Fröhlich W., Schefzyk M., Kumbrink J., Hassel J.C., Berking C., Ziemer M., et al. Checkpoint inhibitor-induced bullous pemphigoid differs from spontaneous bullous pemphigoid. J. Eur. Acad. Dermatol. Venereol. 2024;38:e722–e728. doi: 10.1111/jdv.19860. - DOI - PubMed
    1. Bur D., Patel A.B., Nelson K., Huen A., Pacha O., Phillips R., Heberton M. A retrospective case series of 20 patients with immunotherapy-induced bullous pemphigoid with emphasis on management outcomes. J. Am. Acad. Dermatol. 2022;87:1394–1395. doi: 10.1016/j.jaad.2022.08.001. - DOI - PubMed

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