ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1639853
This article is part of the Research TopicRegulators of the Immune-Tumor Microenvironment: A New Frontier for Cancer ImmunotherapyView all 19 articles
Transglutaminase 2 regulates ovarian cancer metastasis by modulating the immune microenvironment
Provisionally accepted
Dalia Ibrahim1,2*
Melanie Grondin1,2Kristianne Galpin1,2Sara Asif1,3Emily Thompson1,4Sarah Nersesian1,2John Abou-Hamad1,2Maryam Echaibi1,2Galaxia M Rodriguez1,2Pauline Navals4Elizabeth Macdonald1,2Brianna Ryan4David P Cook1,2Jeffrey W Keillor4
Barbara Vanderhyden1,2*- 1Cancer Research Program, Ottawa Hospital Research Institute, Ottawa, Canada
- 2University of Ottawa Department of Cellular and Molecular Medicine, Ottawa, Canada
- 3University of Ottawa Department of Microbiology and Immunology, Ottawa, Canada
- 4University of Ottawa Department of Chemistry and Biomolecular Sciences, Ottawa, Canada
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Ovarian cancer is the most lethal gynecological malignancy. Deepening our knowledge of the interactions within the tumor microenvironment (TME) is important for discovering new targeted treatment strategies. Transglutaminase 2 (TG2) is a protein implicated in many biological and pathophysiological processes, including promoting tumor progression in ovarian cancer. Its role in disease progression has been studied in ovarian cancer cells; however, its role in the ovarian TME is less understood. In this study, for the first time, we assessed the therapeutic potential of novel covalent irreversible small molecule TG2 inhibitors in ovarian cancer. We also further elucidated the role of TG2 in ovarian cancer cells and characterized the contribution of TG2 to the metastatic process of ovarian cancer in the TME. To investigate the transamidation catalytic and GTP binding activities of TG2 in cancer cells, we used several TG2 inhibitors, some of which decreased invasiveness of human ovarian cancer cell lines in vitro and lengthened survival of the SKOV3 xenograft model. Using the ID8 Trp53-/- Brca1-/- and KPCA.B syngeneic mouse models of ovarian cancer, we defined the contribution of TG2 in the TME to the metastatic process. Lack of TG2 in the TME prolonged survival in the ID8 Trp53-/- Brca1-/- metastatic model, but it did not affect survival in the non-metastatic KPCA.B model. Through extensive analysis of the immune composition in both the primary tumor and metastatic ascites in the ID8 Trp53-/- Brca1-/- model, we discovered that the lack of host TG2 resulted in decreased frequency of immunosuppressive tumor-associated macrophages, and increased frequency of T cells, NK cells, and B cells. RNA sequencing of the primary tumors with or without TG2 present in the TME, revealed an enrichment of pathways related to B cell activation and regulation, highlighting a crucial role for TG2 in modulating B cells to enhance survival in the ID8 Trp53-/- Brca1-/- model. Taken together, our findings highlight the importance of TG2 in the TME for ovarian cancer metastasis, potentially through the activation of humoral immunity.
Keywords: ovarian cancer, transglutaminase 2, Immune Modulation, targeted therapy, metastasis
Received: 02 Jun 2025; Accepted: 09 Jul 2025.
Copyright: © 2025 Ibrahim, Grondin, Galpin, Asif, Thompson, Nersesian, Abou-Hamad, Echaibi, Rodriguez, Navals, Macdonald, Ryan, Cook, Keillor and Vanderhyden. 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) or licensor 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.
* Correspondence:
Dalia Ibrahim, Cancer Research Program, Ottawa Hospital Research Institute, Ottawa, Canada
Barbara Vanderhyden, Cancer Research Program, Ottawa Hospital Research Institute, Ottawa, Canada
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