Language

English

Publication Date

1-1-2026

Journal

Frontiers in Immunology

DOI

10.3389/fimmu.2026.1853409

PMID

42292493

PMCID

PMC13260466

PubMedCentral® Posted Date

5-29-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Mesothelin (MSLN) is a GPI-anchored cell surface glycoprotein that is overexpressed in various solid tumors, including mesothelioma, triple-negative breast cancer, colon, ovarian and pancreatic cancer, with restricted normal tissue expression.

Methods: To explore the immunogenicity and immunotherapeutic potential of MSLN to T cells with native receptor specificity, 29 individuals of diverse HLA backgrounds were interrogated for T cell activity against MSLN.

Results: Twenty one (72%) subjects (21/29) mounted a specific T cell response when repetitively challenged with MSLN antigen. Reactive cells were Th1-polarized, polyfunctional, predominantly detected in the CD8+ T cell compartment and cytotoxic toward autologous and MSLN+/HLA-matched tumor cell lines in conventional 2D in vitro assays. Furthermore, these cells produced anti-tumor effects in a novel 3D tumor spheroid model system established to evaluate the potency of reactive cells against tumors including pancreatic, cervical, and colorectal cancer and mesothelioma.

Conclusions: These preclinical findings lay the groundwork for further exploration of MSLN as a potential immunotherapeutic target for T cells via the native T cell receptor.

Keywords

Humans, Mesothelin, GPI-Linked Proteins, Immunotherapy, Neoplasms, Female, Cell Line, Tumor, Antigens, Neoplasm, adoptive T cell immunotherapy of cancer, epitope identification, HLA diversity, HLA restriction, mesothelin, solid tumor, T cell receptor specificity, tumor-associated antigen

Published Open-Access

yes

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