REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1473969
This article is part of the Research TopicMonitoring the Immune/Tumor Microenvironment to Improve Cancer ImmunotherapyView all 8 articles
Tertiary Lymphoid Structures: Exploring Opportunities to Improve Immunotherapy in Ovarian Cancer
Provisionally accepted
Aaron Varghese1,2
Suzanne M Hess2
Shanmuga Reddy Chilakapati2,3Jose Ramon Conejo-Garcia4
AJ Robert McGray5
Emese Zsiros2*- 1Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Rochester Medical Center, Rochester, United States
- 2Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, Illinois, United States
- 3Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, United States
- 4Duke Department of Integrative Immunobiology, Duke University School of Medicine, Durham, United States
- 5Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, United States
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Tertiary lymphoid structures (TLS) are organized ectopic lymphoid clusters of immune cells that develop in non-lymphoid tissue to promote antigen presentation, drive cytotoxic immune responses, and enhance humoral immunity via B cell clonal expansion. Their presence within the tumor microenvironment (TME) correlates with increased patient survival and an improved response to immune checkpoint inhibitors (ICIs), positioning TLS as potential predictive and prognostic biomarkers. Despite the widespread use of ICIs across various cancers, their effectiveness remains limited in gynecological malignancies, including ovarian cancer (OC), a notably challenging disease characterized by poor responses to both single and combination ICI therapies. Interestingly, the infiltration of T cells into the OC TME is linked to enhanced progression-free survival (PFS) and overall survival (OS), yet an immunosuppressive TME frequently impedes therapeutic efficacy, suggesting cell activity within localized immune niches can impact antitumor immunity. This review explores the roles of TLS, their maturity, functionality, identification, and related gene signatures; specific immune cells and cytokines that play a role in TLS formation and antitumor response; and other modifiable elements, including gut microbiota, that may drive improving OC survival by leveraging a TLS-driven antitumor response to bolster immunotherapy outcomes.
Keywords: tertiary lymphoid structures, ovarian cancer, Immunotherapy, Tumor Microenvironment, gut microbiome, biomarker
Received: 31 Jul 2024; Accepted: 24 Apr 2025.
Copyright: © 2025 Varghese, Hess, Chilakapati, Conejo-Garcia, McGray and Zsiros. 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: Emese Zsiros, Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, Illinois, United States
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.