Boosting ovarian cancer immunotherapy via discoidin domain receptor 2 blockade and CD28 x mucin 1 bispecific antibodies.
11 affiliations
- 1Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy.
- 2Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy.
- 3Institute of Molecular Biology and Pathology (IBPM), CNR, Rome, Italy.
- 4Department of Internal Medicine and Medical Specialties - DIMI, University of Genova, Genova, Italy.
- 5LIFE Institute for Research and Health Care - Santa Lucia IRCCS, Rome, Italy.
- 6Department of Basic and Applied Sciences for Engineering, Sapienza University of Rome, Rome, Italy.
- 7Research Center for Nanotechnology applied to Engineering, Sapienza University of Rome, Rome, Italy.
- 8Università Cattolica del Sacro Cuore, Rome, Italy.
- 9Unit of Oncological Gynaecology, Department of Woman, Child and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
- 10Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy. [email protected].
- 11Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy. [email protected].
Abstract
Background
Serous ovarian carcinoma (SOC) is a highly aggressive gynaecological malignancy with frequent relapse and the development of chemoresistance. A major feature of SOC tumour microenvironment is the accumulation of dense collagen fibres, which promote tumour progression and immune evasion. Discoidin domain receptor 2 (DDR2), a collagen-binding receptor tyrosine kinase activated by fibrillar collagens, mediates extracellular matrix-associated signalling involved in tumour progression and immune exclusion. However, its role in limiting antitumour immunity and contributing to immunotherapy resistance in SOC remains poorly understood.Methods
We investigated the impact of DDR2 blockade on SOC-specific T cell activity and on the efficacy of recombinant bispecific antibodies (BsAbs) targeting CD28 and mucin 1 (MUC1). SOC-specific T cells were generated from healthy donor peripheral blood mononuclear cells and assessed for recruitment, activation, and cytotoxicity against low-grade (OVCA433) and high-grade (OVCAR3) SOC cell lines under different treatment conditions.Results
DDR2 inhibition enhanced SOC-specific T cell responses by remodelling the collagen matrix, favouring their recruitment, activation and cytotoxic activity against both low- and high-grade SOC cells. Moreover, combined treatment with DDR2 blockade and CD28xMUC1 BsAbs significantly increased the recruitment of SOC-specific T cells, granzyme B release, caspase-3 activation, and cytokine production.Conclusions
DDR2 blockade mitigates collagen-mediated immune exclusion and enhances the efficacy of CD28xMUC1 BsAb-based immunotherapy in SOC models. These findings provide a mechanistic rationale for further investigation of combined DDR2 targeting and CD28×MUC1 costimulatory strategies to improve ovarian cancer immunotherapy.
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BibTeX
@article{kunkl2026boosting,
title = {{Boosting ovarian cancer immunotherapy via discoidin domain receptor 2 blockade and CD28 x mucin 1 bispecific antibodies.}},
author = {Martina Kunkl and Silvia Malatesta and Flavia Ottavi and Ilenia Masi and Manolo Sambucci and Virginia Vigiano Benedetti and Maria Egle De Stefano and Martina Leopizzi and Maria Teresa Fiorillo and Marco Rossi and Francesco Mura and Anacleto Proietti and Enrica Martinelli and Camilla Nero and Anna Fagotti and Giovanna Borsellino and Luca Battistini and Valerio Licursi and Francesco Spallotta and Laura Rosanò and Loretta Tuosto},
journal = {BMC medicine},
year = {2026},
month = aug,
doi = {10.1186/s12916-026-05183-2},
url = {https://europepmc.org/article/MED/42958545},
note = {CC BY},
}
RIS
TY - JOUR
TI - Boosting ovarian cancer immunotherapy via discoidin domain receptor 2 blockade and CD28 x mucin 1 bispecific antibodies.
AU - Martina Kunkl
AU - Silvia Malatesta
AU - Flavia Ottavi
AU - Ilenia Masi
AU - Manolo Sambucci
AU - Virginia Vigiano Benedetti
AU - Maria Egle De Stefano
AU - Martina Leopizzi
AU - Maria Teresa Fiorillo
AU - Marco Rossi
AU - Francesco Mura
AU - Anacleto Proietti
AU - Enrica Martinelli
AU - Camilla Nero
AU - Anna Fagotti
AU - Giovanna Borsellino
AU - Luca Battistini
AU - Valerio Licursi
AU - Francesco Spallotta
AU - Laura Rosanò
AU - Loretta Tuosto
PY - 2026
DA - 2026/08/24
JO - BMC medicine
DO - 10.1186/s12916-026-05183-2
UR - https://europepmc.org/article/MED/42958545
AB - Background Serous ovarian carcinoma (SOC) is a highly aggressive gynaecological malignancy with frequent relapse and the development of chemoresistance. A major feature of SOC tumour microenvironment is the accumulation of dense collagen fibres, which promote tumour progression and immune evasion. Discoidin domain receptor 2 (DDR2), a collagen-binding receptor tyrosine kinase activated by fibrillar collagens, mediates extracellular matrix-associated signalling involved in tumour progression and immune exclusion. However, its role in limiting antitumour immunity and contributing to immunotherapy resistance in SOC remains poorly understood.Methods We investigated the impact of DDR2 blockade on SOC-specific T cell activity and on the efficacy of recombinant bispecific antibodies (BsAbs) targeting CD28 and mucin 1 (MUC1). SOC-specific T cells were generated from healthy donor peripheral blood mononuclear cells and assessed for recruitment, activation, and cytotoxicity against low-grade (OVCA433) and high-grade (OVCAR3) SOC cell lines under different treatment conditions.Results DDR2 inhibition enhanced SOC-specific T cell responses by remodelling the collagen matrix, favouring their recruitment, activation and cytotoxic activity against both low- and high-grade SOC cells. Moreover, combined treatment with DDR2 blockade and CD28xMUC1 BsAbs significantly increased the recruitment of SOC-specific T cells, granzyme B release, caspase-3 activation, and cytokine production.Conclusions DDR2 blockade mitigates collagen-mediated immune exclusion and enhances the efficacy of CD28xMUC1 BsAb-based immunotherapy in SOC models. These findings provide a mechanistic rationale for further investigation of combined DDR2 targeting and CD28×MUC1 costimulatory strategies to improve ovarian cancer immunotherapy.
SN - 1741-7015
ER -