University of Oulu

Petruk N, Siddiqui A, Tadayon S, Määttä J, Mattila PK, Jukkola A, Sandholm J and Selander KS (2023) CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases. Front. Immunol. 14:1179022. doi: 10.3389/fimmu.2023.1179022

CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases

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Author: Petruk, Nataliia1; Siddiqui, Arafat1,2; Tadayon, Sina3,4;
Organizations: 1Institute of Biomedicine, University of Turku, Turku, Finland
2Western Cancer Centre FICAN West, Turku, Finland
3MediCity Research Laboratory, University of Turku, Turku, Finland
4InFLAMES Research Flagship Center, University of Turku, Turku, Finland
5Turku Center for Disease Modeling, University of Turku, Turku, Finland
6Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
7Department of Oncology, Tampere University Hospital, Tays Cancer Center, Tampere, Finland
8Department of Oncology and Radiation Therapy, Oulu University Hospital, Oulu, Finland
9Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 13.8 MB)
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Language: English
Published: Frontiers Media, 2023
Publish Date: 2023-09-12


Introduction: Bisphosphonates (BPs) are bone-protecting osteoclast inhibitors, typically used in the treatment of osteoporosis and skeletal complications of malignancies. When given in the adjuvant setting, these drugs may also prevent relapses and prolong overall survival in early breast cancer (EBC), specifically among postmenopausal patients. Because of these findings, adjuvant nitrogen-containing BPs (N-BPs), such as zoledronate (ZOL), are now the standard of care for high-risk EBC patients, but there are no benefit-associated biomarkers, and the efficacy remains low. BPs have been demonstrated to possess anti-tumor activities, but the mechanisms by which they provide the beneficial effects in EBC are not known.

Methods: We used stably transfected 4T1 breast cancer cells together with suppression of CD73 (sh-CD73) or control cells (sh-NT). We compared ZOL effects on tumor growth and infiltrating lymphocytes (TILs) into tumors and lung metastases using two mouse models. B cell depletion was performed using anti-CD20 antibody.

Results: Sh-CD73 4T1 cells were significantly more sensitive to the growth inhibitory effects of n-BPs in vitro. However, while ZOL-induced growth inhibition was similar between the tumor groups in vivo, ZOL enhanced B and T lymphocyte infiltration into the orthotopic tumors with down-regulated CD73. A similar trend was detected in lung metastases. ZOL-induced tumor growth inhibition was found to be augmented with B cell depletion in sh-NT tumors, but not in sh-CD73 tumors. As an internal control, ZOL effects on bone were similar in mice bearing both tumor groups.

Discussion: Taken together, these results indicate that ZOL modifies TILs in breast cancer, both in primary tumors and metastases. Our results further demonstrate that B cells may counteract the growth inhibitory effects of ZOL. However, all ZOL-induced TIL effects may be influenced by immunomodulatory characteristics of the tumor.

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Series: Frontiers in immunology
ISSN: 1664-3224
ISSN-E: 1664-3224
ISSN-L: 1664-3224
Volume: 14
Article number: 1179022
DOI: 10.3389/fimmu.2023.1179022
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This study was supported by Academy of Finland (308375).
Copyright information: © 2023 Petruk, Siddiqui, Tadayon, Määttä, Mattila, Jukkola, Sandholm and Selander. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.