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Prognostic Value of Lymphoid Infiltration and Aggregation in Cervical Cancer
by
, ,
Grace Gorecki
1,†
,
Macy Hale
1,†,
Sarah Taylor
2,
Geyon Garcia
3,
Ian P MacFawn
4,5,
T. Rinda Soong
6,
Tullia C. Bruno
4,‡ and
Lan Coffman
1,2,7,*,‡ 1
Division of Hematology and Oncology, University of Pittsburgh, Pittsburgh, PA 15261, USA
2
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, and Reproductive Science, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
3
Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA
4
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
5
Department of Biology, Grove City College, Grove City, PA 16127, USA
6
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pittsburgh, PA 15213, USA
7
Magee Women’s Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to the work as co-first author.
‡
These authors contributed equally to the work as co-senior author.
Cancers 2026, 18(1), 129; https://doi.org/10.3390/cancers18010129 (registering DOI)
Submission received: 25 November 2025
/
Revised: 22 December 2025
/
Accepted: 27 December 2025
/
Published: 30 December 2025
(This article belongs to the Special Issue Immune Biomarkers and Checkpoint Inhibitors: Advancing Immunotherapy in Gynecologic Cancers)
Simple Summary
The immune system plays an important role in cervical cancer, and immunotherapies are emerging as new treatment options in this disease. However, it is unclear which cervical cancer patients will respond to immunotherapy and how the makeup of immune cells within the cancer impacts the behavior of cervical cancer. In this work, we investigate the presence of specific immune structures, called tertiary lymphoid structures, within cervical cancer samples. We demonstrate that these structures are most beneficial when organized into well-defined clusters with specific signaling molecules such as CXCL13. Indeed, the presence of these immune structures with high CXCL13 levels is correlated with improved survival. This work highlights the importance of the spatial organization of immune cells within the cervical cancer environment and presents these findings as potential prognostic biomarkers and future targets to improve immunotherapy in cervical cancer.
Abstract
Background/objectives: Understanding the immune landscape in cervical cancer is critical to the development of improved therapeutics. This study investigated the immune microenvironment in early-stage cervical cancer with a focus on B and T cell immune aggregates, i.e., lymphoid aggregates (LAs) and tertiary lymphoid structures (TLSs). Methods: Using multispectral imaging, we interrogated a cohort of patients with clinical stage I squamous or adenocarcinoma of the cervix with a focus on T and B cell spatial location and organization. Despite early-stage disease, recurrence was common at 37%, highlighting the need to identify patients at high risk for recurrence. Results: We demonstrated that high CD8+ T cell infiltration correlated significantly with improved overall survival (OS), particularly in patients with adenocarcinoma histology. CD8+ T cells colocalized with B cells, suggesting the formation of a more sophisticated cellular neighborhood, i.e., TLS, which has prognostic benefit in other solid tumors. CXCL13, a chemokine associated with TLS formation, correlated with improved recurrence-free survival. The combination of high CXCL13 and lymphoid structures correlated with improved OS. However, most immune structures in cervical cancer were lymphoid aggregates (LAs) that lack features of more developed TLS, such as high endothelial venules (HEVs) and germinal centers (GCs), highlighting a lack of full immune activation in this microenvironment. Validation in The Cancer Genome Atlas (TCGA) cohort illustrated similar trends in survival. Conclusion: Collectively, this work demonstrates the prognostic significance of immune infiltration and eventual TLS induction in early cervical cancer and presents potential future therapeutic targets.
Keywords:
cervical cancer; tertiary lymphoid structures; immunotherapy
