# Prognostic Value of Lymphoid Infiltration and Aggregation in Cervical Cancer

## TL;DR

This study shows that organized immune structures in cervical cancer, especially those with high CXCL13 levels, are linked to better survival and could help guide immunotherapy.

## Contribution

The study identifies the prognostic value of spatially organized immune structures and CXCL13 in early-stage cervical cancer.

## Key findings

- High CD8+ T cell infiltration correlates with improved survival in cervical cancer patients.
- CXCL13 levels and the presence of lymphoid structures are associated with better recurrence-free and overall survival.
- Most immune structures in cervical cancer lack full immune activation features like HEVs and GCs.

## Abstract

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.

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. Conclusions: Collectively, this work demonstrates the prognostic significance of immune infiltration and eventual TLS induction in early cervical cancer and presents potential future therapeutic targets.