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. 2025 Aug;156(2):463-467.e2.
doi: 10.1016/j.jaci.2025.02.031. Epub 2025 Mar 6.

Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis

Aiko Oka  1 , Aiko I Klingler  2 , Masanori Kidoguchi  3 , Julie A Poposki  2 , Lydia A Suh  2 , Junqin Bai  4 , Whitney W Stevens  2 , Anju T Peters  2 , Leslie C Grammer  2 , Kevin C Welch  4 , Stephanie S Smith  4 , David B Conley  4 , Robert P Schleimer  5 , Robert C Kern  5 , Bruce K Tan  4 , Shigeharu Fujieda  6 , Mitsuhiro Okano  7 , Atsushi Kato  8
Affiliations

Tezepelumab inhibits highly functional truncated thymic stromal lymphopoietin in chronic rhinosinusitis

Aiko Oka et al. J Allergy Clin Immunol. 2025 Aug.

Abstract

Background: Thymic stromal lymphopoietin (TSLP) and its functional cleavage products are elevated in nasal polyps (NPs) and play important roles in type 2 (T2) inflammation in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) by activating myeloid dendritic cells (mDCs) and group 2 innate lymphoid cells (ILC2s). However, whether tezepelumab, a human mAb against TSLP, inhibits functional cleaved TSLP and also the role of TSLP in CRS without nasal polyps (CRSsNP) have not yet been studied.

Objective: We sought to investigate the effects of tezepelumab on cleaved TSLP in CRS.

Methods: The mRNA expression levels for TSLP and T2 markers in ethmoid tissues (ETs) from 31 controls and 118 patients with CRSsNP and in NPs from 53 patients with CRSwNP were measured by quantitative RT-PCR. Cleaved TSLP was prepared from full-length recombinant TSLP by incubation with tissue extracts of NPs and CRSsNP ETs. The effects of tezepelumab on cleaved TSLP-induced inflammation were evaluated using PBMCs by monitoring the production of chemokines (CCL17 and CCL22 for mDCs) and cytokines (IL-5 and IL-13 for ILC2s).

Results: The mRNA expression level of TSLP was elevated not only in NPs but also in ETs from T2 CRSsNP compared with non-T2 CRSsNP and controls, and was positively correlated with T2 markers in CRSsNP (P < .001). CRSsNP ET also truncated and created highly active TSLP products. The activation of mDCs and ILC2s by full-length TSLP and cleaved TSLP created by ET and NP extracts was dose-dependently inhibited by tezepelumab.

Conclusions: TSLP plays a role in T2 inflammation in CRSsNP and CRSwNP. Treatment with tezepelumab may benefit patients with T2 CRS by inhibiting active forms of TSLP.

Keywords: CRSsNP; CRSwNP; T2 inflammation; TSLP; Tezepelumab; chronic rhinosinusitis; nasal polyps; posttranslational modification.

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Conflict of interest statement

Disclosure statement This research was supported in part by AstraZeneca, National Institutes of Health grants (grant nos. P01AI145818 and R01AI137174), the Japan Agency for Medical Research and Development (no. JP23jf0126005), the Uehara Memorial Foundation, and the Ernest S. Bazley Foundation. Disclosure of potential conflict of interest: W. W. Stevens has served on advisory boards for GlaxoSmithKline, Genentech, and Bristol Myers Squibb. A. T. Peters has served on advisory boards for Sanofi-Genzyme/Regeneron, OptiNose, AstraZeneca, Novartis, and GlaxoSmithKline; and has research support from OptiNose and Sanofi-Regeneron. L. C. Grammer reports personal fees from Astellas Pharmaceuticals. K. C. Welch reports consultant fees from Baxter, OptiNose, and Acclarent. R. P. Schleimer reports personal fees from Intersect ENT, Merck, GlaxoSmithKline, Sanofi, AstraZeneca/Medimmune, Genentech, Actobio Therapeutics, Lyra Therapeutics, Astellas Pharma, Inc, and Otsuka, Inc; and has royalty rights to Siglec-8– and Siglec-8 ligand–related patents licensed by Johns Hopkins University to Allakos, Inc. R. C. Kern reports consulting fees from Lyra Therapeutics, Medtronic, GlaxoSmithKline, Genentech, and Sanofi-Regeneron. B. K. Tan reports personal fees from Sanofi-Regeneron/Genzyme and GlaxoSmithKline. A. Kato has served on an advisory board for AstraZeneca; and has received research grants from Regeneron and AstraZeneca. The rest of the authors declare that they have no relevant conflicts of interest.

References

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