The OX40-OX40L Co-stimulatory pathway in dermatology: emerging frontiers for therapeutic approaches

Ishii N, Takahashi T, Soroosh P, Sugamura K. OX40–OX40 Ligand Interaction in T-Cell-Mediated Immunity and Immunopathology. In: Adv Immunol [Internet]. 2010. pp. 63–98. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0065277610050030

Taefehshokr N, Baradaran B, Baghbanzadeh A, Taefehshokr S. Promising approaches in cancer immunotherapy. Immunobiology [Internet]. 2020;225(2):151875. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0171298519302517

Sadrolashrafi K, Guo L, Kikuchi R, Hao A, Yamamoto RK, Tolson HC et al. An OX-Tra’Ordinary Tale: The Role of OX40 and OX40L in Atopic Dermatitis. Cells [Internet]. 2024;13(7):587. Available from: https://www.mdpi.com/2073-4409/13/7/587

van der Zwan M, Hesselink DA, van den Hoogen MWF, Baan CC. Costimulation Blockade in Kidney Transplant Recipients. Drugs [Internet]. 2020;80(1):33–46. Available from: http://link.springer.com/https://doi.org/10.1007/s40265-019-01226-6

Akiba H, Miyahira Y, Atsuta M, Takeda K, Nohara C, Futagawa T et al. Critical Contribution of Ox40 Ligand to T Helper Cell Type 2 Differentiation in Experimental Leishmaniasis. J Exp Med [Internet]. 2000;191(2):375–80. Available from: https://rupress.org/jem/article/191/2/375/51003/Critical-Contribution-of-Ox40-Ligand-to-T-Helper

Tripathi T, Yin W, Xue Y, Zurawski S, Fujita H, Hanabuchi S et al. Central Roles of OX40L–OX40 Interaction in the Induction and Progression of Human T Cell–Driven Acute Graft-versus-Host Disease. Immunohorizons [Internet]. 2019;3(3):110–20. Available from: https://academic.oup.com/immunohorizons/article/3/3/110/7823469

Griseri T, Asquith M, Thompson C, Powrie F. OX40 is required for regulatory T cell–mediated control of colitis. Journal of Experimental Medicine [Internet]. 2010;207(4):699–709. Available from: https://rupress.org/jem/article/207/4/699/40704/OX40-is-required-for-regulatory-T-cell-mediated

Thapa B, Kato S, Nishizaki D, Miyashita H, Lee S, Nesline MK et al. OX40/OX40 ligand and its role in precision immune oncology. Cancer and Metastasis Reviews [Internet]. 2024;43(3):1001–13. Available from: https://link.springer.com/https://doi.org/10.1007/s10555-024-10184-9

Fu Y, Lin Q, Zhang Z, Zhang L. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity. Acta Pharm Sin B [Internet]. 2020;10(3):414–33. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2211383519306161

Lai C, August S, Albibas A, Behar R, Cho SY, Polak ME, et al. OX40 + Regulatory T cells in cutaneous squamous cell carcinoma suppress effector T-Cell responses and associate with metastatic potential. Clin Cancer Res. 2016;22(16):4236–48.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kawana Y, Suga H, Kamijo H, Miyagaki T, Sugaya M, Sato S. Roles of OX40 and OX40 Ligand in Mycosis Fungoides and Sézary Syndrome. Int J Mol Sci [Internet]. 2021;22(22):12576. Available from: https://www.mdpi.com/1422-0067/22/22/12576

Providence H, Services. ClinicalTrials.gov. 2018 [cited 2025 Oct 24]. Study of MEDI0562 Prior to Surgical Resection in Head and Neck Squamous Cell Carcinoma (HNSCC) or Melanoma. Available from: https://clinicaltrials.gov/study/NCT03336606

Diab A, Hamid O, Thompson JA, Ros W, Eskens FALM, Doi T et al. A Phase I, open-label, dose-escalation study of the OX40 agonist ivuxolimab in patients with locally advanced or metastatic cancers. Clin Cancer Res [Internet]. 2022;28(1):71–83. Available from: https://aacrjournals.org/clincancerres/article/28/1/71/675026/A-Phase-I-Open-Label-Dose-Escalation-Study-of-the

Peng W, Williams LJ, Xu C, Melendez B, McKenzie JA, Chen Y et al. Anti-OX40 antibody directly enhances the function of tumor-reactive CD8 + T Cells and synergizes with PI3Kβ inhibition in PTEN loss melanoma. Clin Cancer Res [Internet]. 2019;25(21):6406–16. Available from: https://aacrjournals.org/clincancerres/article/25/21/6406/82083/Anti-OX40-Antibody-Directly-Enhances-The-Function

Kuang Z, Jing H, Wu Z, Wang J, Li Y, Ni H et al. Development and characterization of a novel anti-OX40 antibody for potent immune activation. Cancer Immunol, Immunother [Internet]. 2020;69(6):939–50. Available from: http://link.springer.com/https://doi.org/10.1007/s00262-020-02501-2

Ma Y, Li J, Wang H, Chiu Y, Kingsley CV, Fry D et al. Combination of PD-1 inhibitor and OX40 agonist induces tumor rejection and immune memory in mouse models of pancreatic cancer. Gastroenterology [Internet]. 2020;159(1):306–319.e12. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0016508520303395

Lee DH. Update of early phase clinical trials in cancer immunotherapy. BMB Rep [Internet]. 2021;54(1):70–88. Available from: http://www.bmbreports.org/journal/view.html?doi=10.5483/BMBRep.2021.54.1.242

Duhen R, Ballesteros-Merino C, Frye AK, Tran E, Rajamanickam V, Chang SC et al. Neoadjuvant anti-OX40 (MEDI6469) therapy in patients with head and neck squamous cell carcinoma activates and expands antigen-specific tumor-infiltrating T cells. Nat Commun [Internet]. 2021;12(1):1047. Available from: https://www.nature.com/articles/s41467-021-21383-1

Iriki H, Takahashi H, Amagai M. Diverse role of OX40 on T cells as a therapeutic target for skin diseases. J Investig Dermatol [Internet]. 2023;143(4):545–53. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0022202X22028366

Yao W, German B, Chraa D, Braud A, Hugel C, Meyer P et al. Keratinocyte-derived cytokine TSLP promotes growth and metastasis of melanoma by regulating the tumor-associated immune microenvironment. JCI Insight [Internet]. 2022;7(21). Available from: https://insight.jci.org/articles/view/161438

Yang Y, Liu C, Peng W, Lizée G, Overwijk WW, Liu Y et al. Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40. Blood [Internet]. 2012;120(23):4533–43. Available from: https://ashpublications.org/blood/article/120/23/4533/30905/Antitumor-Tcell-responses-contribute-to-the

Sibilano R, Pucillo C, Frossi B. Modulation of FcεRI-dependent mast cell response by OX40L. In: Methods Mol Biol [Internet]. 2014. pp. 23–30. Available from: https://link.springer.com/https://doi.org/10.1007/978-1-4939-0669-7_3

Criado RFJ, Criado PR, Pagliari C, Sotto MN, Machado Filho CD, Bianco B. M2 macrophage polarization in chronic spontaneous urticaria refractory to antihistamine treatment. Allergol Int [Internet]. 2021;70(4):504–6. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1323893021000435

Bansal-Pakala P, Halteman BS, Cheng MHY, Croft M. Costimulation of CD8 T cell responses by OX40. The J Immunol [Internet]. 2004;172(8):4821–5. Available from: https://academic.oup.com/jimmunol/article/172/8/4821/8060133

Chen Y, Griffiths CEM, Bulfone-Paus S. Exploring mast Cell–CD8 T cell interactions in inflammatory skin diseases. Int J Mol Sci [Internet]. 2023;24(2):1564. Available from: https://www.mdpi.com/1422-0067/24/2/1564

Deng R, Chen X, Zhang Y, Bian F, Gao N, Hu J et al. Short ragweed pollen promotes M2 macrophage polarization via TSLP/TSLPR/OX40L signaling in allergic inflammation. Mucosal Immunol [Internet]. 2019;12(5):1141–9. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1933021922004378

Lee YK, Mukasa R, Hatton RD, Weaver CT. Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol [Internet]. 2009;21(3):274–80. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0952791509001034

Suurmond J, Habets KLL, Dorjée AL, Huizinga TW, Toes REM. Expansion of Th17 cells by human mast cells is driven by inflammasome-Independent IL-1β. The J Immunol [Internet]. 2016;197(11):4473–81. Available from: https://academic.oup.com/jimmunol/article/197/11/4473/7973663

Elieh Ali Komi D, Grauwet K. Role of mast cells in regulation of T cell responses in experimental and clinical settings. Clin Rev Allergy Immunol. 2018;54(3):432–45.

Article  CAS  PubMed  Google Scholar 

Piconese S, Gri G, Tripodo C, Musio S, Gorzanelli A, Frossi B et al. Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood [Internet]. 2009;114(13):2639–48. Available from: https://ashpublications.org/blood/article/114/13/2639/26414/Mast-cells-counteract-regulatory-Tcell-suppression

Hong GU, Lim JY, Kim NG, Shin JH, Ro JY. IgE and IgA produced by OX40–OX40L or CD40–CD40L interaction in B cells–mast cells re-activate FcεRI or FcαRI on mast cells in mouse allergic asthma. Eur J Pharmacol [Internet]. 2015;754:199–210. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0014299915001302

Sibilano R, Gri G, Frossi B, Tripodo C, Suzuki R, Rivera J et al. Technical advance: Soluble OX40 molecule mimics regulatory T cell modulatory activity on FcɛRI-dependent mast cell degranulation. J Leukoc Biol [Internet]. 2011;90(4):831–8. Available from: https://academic.oup.com/jleukbio/article/90/4/831/6960294

Diotallevi F, Gioacchini H, De Simoni E, Marani A, Candelora M, Paolinelli M et al. Vitiligo, from Pathogenesis to therapeutic advances: State of the Art. Int J Mol Sci [Internet]. 2023;24(5):4910. Available from: https://www.mdpi.com/1422-0067/24/5/4910

Gay-Mimbrera J, Lozano-Ojalvo D, Gómez-Arias PJ, Rivera-Ruiz I, Aguilar-Luque M, Mochón-Jiménez C et al. Comprehensive single-cell chromatin and transcriptomic profiling of peripheral immune cells in nonsegmental vitiligo. British Journal of Dermatology [Internet]. 2025;193(1):115–24. Available from: https://academic.oup.com/bjd/article/193/1/115/7994225

Matsumura Y, Hori T, Nishigori C, Shirogane K, Toda KI, Uchiyama T et al. Expression of CD134 and CD134 ligand in lesional and nonlesional psoriatic skin. Arch Dermatol Res [Internet]. 2003;294(12):563–6. Available from: http://link.springer.com/https://doi.org/10.1007/s00403-002-0363-6

Guo R, Zhang T, Meng X, Lin Z, Lin J, Gong Y et al. Lymphocyte mass cytometry identifies a CD3-CD4 + cells subset with a potential role in psoriasis. JCI Insight [Internet]. 2019;2019. Available from: http://insight.jci.org/articles/view/125306

Papp KA, Gooderham MJ, Girard G, Raman M, Strout V. Phase I randomized study of KHK4083, an anti-OX40 monoclonal antibody, in patients with mild to moderate plaque psoriasis. J Eur Acad Dermatol Venereol [Internet]. 2017;31(8):1324–32. Available from: https://onlinelibrary.wiley.com/doi/https://doi.org/10.1111/jdv.14313

Iriki H, Takahashi H, Wada N, Nomura H, Mukai M, Kamata A et al. Peripheral tolerance by Treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus. In: Proceedings of the National Academy of Sciences [Internet]. 2021;118(49):7–10. Available from: https://doi.org/10.1073/pnas.2026763118

Bertolini M, Zilio F, Rossi A, Kleditzsch P, Emelianov VE, Gilhar A et al. Abnormal interactions between perifollicular mast cells and CD8 + T-cells may contribute to the pathogenesis of alopecia areata. Eckert RL, editor. PLoS One [Internet]. 2014;9(5):e94260. Available from: https://doi.org/10.1371/journal.pone.0094260

Remedios KA, Zirak B, Sandoval PM, Lowe MM, Boda D, Henley E et al. The TNFRSF members CD27 and OX40 coordinately limit TH17 differentiation in regulatory T cells. Sci Immunol. 2018;3(30):eaau2042.

Navrazhina K, Renert-Yuval Y, Khattri S, Hamade H, Meariman M, Andrews E et al. Tape strips detect molecular alterations and cutaneous biomarkers in skin of patients with hidradenitis suppurativa. J Am Acad Dermatol [Internet]. 2024;90(4):749–58. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0190962223032632

Papadopoulos C, Terzis G, Papadimas GK, Manta P. OX40-OX40L expression in idiopathic inflammatory myopathies. Anal Quant Cytopathol Histpathol [Internet]. 2013;35(1):17–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23469620

Wen M, Ying Y, Xiao X, Arnold PR, Wang G, Chu X et al. Ox40-Cre–mediated deletion of BRD4 reveals an unexpected phenotype of hair follicle stem cells in alopecia. JCI Insight [Internet]. 2022;7(23). Available from: https://insight.jci.org/articles/view/164534

Miyagawa F, Nakamura Y, Miyashita K, Iioka H, Himuro Y, Ogawa K et al. Preferential expression of CD134, an HHV-6 cellular receptor, on CD4T cells in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS). J Dermatol Sci [Internet]. 2016;83(2):151–4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0923181116300706

Mitsui Y, Shinkuma S, Nakamura-Nishimura Y, Ommori R, Ogawa K, Miyagawa F et al. Serum Soluble OX40 as a diagnostic and prognostic biomarker for drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. J Allergy Clin Immunol Pract [Internet]. 2022;10(2):558–565.e4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2213219821011958

Humphreys IR, Walzl G, Edwards L, Rae A, Hill S, Hussell T. A critical role for OX40 in T Cell–mediated immunopathology during lung viral infection. J Exp Med. 2003;198(8):1237–42.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Guttman-Yassky E, Esfandiari E, Mano H, Arai T, Irvine AD, Cork MJ et al. Durable improvements in atopic dermatitis in the head and neck and across other anatomic regions with rocatinlimab. Arch Dermatol Res [Internet]. 2024;316(10):747. Available from: https://link.springer.com/https://doi.org/10.1007/s00403-024-03426-x

Guttman-Yassky E, Simpson EL, Reich K, Kabashima K, Igawa K, Suzuki T, et al. An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study. Lancet. 2023;401(10372):204–14.

Article  CAS  PubMed  Google Scholar 

Weidinger S, Bieber T, Cork MJ, Reich A, Wilson R, Quaratino S, et al. Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial. Br J Dermatol. 2023;189(5):531–9.

Article  CAS  PubMed  Google Scholar 

Weidinger S, Blauvelt A, Papp KA, Reich A, Lee CH, Worm M et al. Phase 2b randomized clinical trial of amlitelimab, an anti-OX40 ligand antibody, in patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol [Internet]. 2025;155(4):1264–75. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0091674924011758

Rewerska B, Sher LD, Alpizar S, Pauser S, Pulka G, Mozaffarian N et al. Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis. J Allergy Clin Immunol: Globa [Internet]. 2023;3(1):100195. Available from: https://linkinghub.elsevier.com/retrieve/pii/S2772829323001200

Nakajima S, Yonekura S, Kabashima K. Targeting the OX40-OX40L pathway: A new era in atopic dermatitis management by T-cell rebalancing. J Allergy Clin Immunol [Internet]. 2025;155(4):1211–3. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0091674925001745

Sullivan RJ, Yeku OO, Teoh D, Gupta S, Matei D, Laino AS et al. First-in-human phase I/II, open-label study of mRNA-2416 alone or combined with durvalumab in patients with advanced solid tumors and ovarian cancer. Oncologist. 2025;30(6):oyaf115.

Davis EJ, Martin-Liberal J, Kristeleit R, Cho DC, Blagden SP, Berthold D, et al. First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors. J Immunother Cancer. 2022;10(10):e004235.

Article  PubMed  PubMed Central  Google Scholar 

Alvarenga JM, Bieber T, Torres T. Emerging Biologic Therapies for the Treatment of Atopic Dermatitis. Drugs [Internet]. 2024;84(11):1379–94. Available from: https://link.springer.com/https://doi.org/10.1007/s40265-024-02095-4

Comments (0)

No login
gif