What question did this study set out to answer?

The research aims to explore the relationship between CCL21+ CAFs and B-cell recruitment in the context of TLS maturation in penile squamous cell carcinoma.

March 19, 2026Open Access

Association of CCL21+ CAFs with B-cell recruitment and TLS maturation in penile squamous cell carcinoma

Key Points

The research aims to explore the relationship between CCL21+ CAFs and B-cell recruitment in the context of TLS maturation in penile squamous cell carcinoma.
Integrated H&E staining, multiplex immunohistochemical (mIHC) analysis, and spatial transcriptomics for TLS profiling.
Performed single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing to assess immune features.
Quantified TLS maturity using an AUCell germinal centre-like signature.
Examined spatial distribution of CCL21+ CAFs in relation to B-cell locations.
Correlated CCL21 expression and CAF signatures with clinical outcomes.
Identified a significant correlation between the presence of mature TLSs and improved survival rates.
CCL21+ CAFs were enriched in mature TLS regions and linked to B-cell activation and migration patterns.
Higher levels of CCL21 expression and CAF signature scores were associated with favorable patient outcomes.
The CCL21-CCR7 signaling axis was highlighted as a potential therapeutic target.

Abstract

Penile squamous cell carcinoma (PSCC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. Tertiary lymphoid structures (TLSs) can support antitumour immunity, yet TLS maturation and maturation-associated stromal determinants in PSCC remain unclear. Here, we integrated hematoxylin and eosin (H mIHC further confirmed dense CCL21+ACTA2+ CAFs near CD20+ aggregates. Along an inferred iTLS-to-mTLS continuum, the abundance of CCL21+ CAFs increased, and the expression of chemokines increased. Spatial and transcriptomic analyses further linked B-cell chemotaxis- and activation-related signatures to the CCL21-CCR7 axis, accompanied by germinal centre-like B-cell features. Clinically, higher CCL21 expression, elevated CCL21+ CAF signature scores, and stronger CCL21-CCR7 signatures in B cells were associated with favourable outcomes. Together, these data suggest that CCL21+ CAFs or CCL21 are potential prognostic biomarkers for risk stratification and immune microenvironment profiling and highlight the CCL21-CCR7 axis as a candidate pathway for therapeutic modulation of TLS maturity in PSCC.

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