# Secondary follicle-like TLS as a protective factor in pMMR rectal cancer: insights into its regional distribution and prognostic value

## TL;DR

This study shows that secondary follicle-like TLS in rectal cancer are linked to better survival and could be a useful biomarker for prognosis.

## Contribution

The study identifies secondary follicle-like TLS as an independent predictor of survival in pMMR rectal cancer.

## Key findings

- Secondary follicle-like TLS infiltration is associated with improved survival in pMMR rectal cancer patients.
- Early TLS infiltration correlates with poorer patient outcomes.
- TLS maturation subtypes are more abundant in the invasive margin than in the central tumor region.

## Abstract

Mismatch repair–proficient rectal cancer (pMMR RC) is characterized by limited effective therapeutic options and an unfavorable prognosis, largely attributed to the complexity of the tumor immune microenvironment. Tertiary lymphoid structures (TLSs), which are ectopic lymphoid aggregates that develop within tumors, constitute a crucial component of this microenvironment and have shown considerable prognostic significance. However, the maturation heterogeneity of TLS subtypes within the tumor immune microenvironment, as well as their associations with clinicopathological characteristics and patient outcomes, remain poorly defined. This study aimed to comprehensively characterize the spatial distribution patterns and prognostic relevance of TLS subtypes in patients with pMMR RC.

We retrospectively analysed tissue sections from 155 patients with pMMR RC who underwent radical resection. TLS maturation subtypes were identified by using hematoxylin and eosin staining and immunohistochemistry, with their spatial distribution quantified and associated with prognosis.

The number of all TLS maturation subtypes in the invasive margin was significantly higher than that in the central tumor region (invasive margin vs central tumor region, P < 0.001). Among these, primary follicle-like TLS exhibited the greatest abundance across all tumor regions. Univariate survival analysis revealed that a higher infiltration of secondary follicle-like TLS across all tumor regions was significantly associated with improved survival, whereas increased early TLS infiltration was associated with poorer outcomes. Multivariate analysis further confirmed that the overall infiltration level of secondary follicle-like TLS was an independent predictor of both overall survival and disease-free survival in patients with pMMR RC.

Secondary follicle-like TLS infiltration independently predicts survival in pMMR RC, underscoring its potential as a prognostic biomarker and immunotherapeutic target.