Intratumoral tertiary lymphoid structure (TLS) maturation is influenced by draining lymph nodes of lung cancer

BackgroundTertiary lymphoid structure (TLS) is an organized infiltration of immune cells, showing features of germinal center (GC) commonly seen in secondary lymphoid organs. However, its relationship with tumor-draining lymph nodes (TDLNs) has not been studied and we hypothesized that TDLN may influence maturation of intratumoral TLS in non-small cell lung cancer (NSCLC).MethodsTissue slides of 616 patients that had undergone surgeries were examined. Cox proportional hazard regression model was used to assess risk factors of patients' survival, and logistic regression model was used for their relationship with TLS. Single-cell RNA-sequencing (scRNA-seq) was employed to explore transcriptomic features of TDLNs. Immunohistochemistry, multiplex immunofluorescence and flow cytometry were performed to analyze cellular composition. Cellular components of NSCLC samples from The Cancer Genome Atlas database were inferred with Microenvironment Cell Populations-counter (MCP-counter) method. Murine NSCLC models were used to dissect underlying mechanisms for relationship between TDLN and TLS maturation.ResultsWhile GC(+) TLS was associated with better prognosis, GC(-) TLS was not. TDLN metastasis reduced the prognostic relevance of TLS, and was associated with less GC formation. Primary tumor sites showed reduced B cell infiltration in TDLN-positive patients, and scRNA-seq revealed diminished memory B cell formation in tumor-invaded TDLNs, together with an emphasis on weakened interferon (IFN)-gamma response. Murine NSCLC models revealed that IFN-gamma signaling is involved in memory B cell differentiation in TDLNs and GC formation in primary tumors.ConclusionsOur research emphasizes the influence of TDLN on intratumoral TLS maturation and suggests a role of memory B cells and IFN-gamma signaling in this communication.

Automated summary

The study found that tumor-draining lymph nodes (TDLN) may influence the maturation of intratumoral tertiary lymphoid structures (TLS) in non-small cell lung cancer (NSCLC). Further research revealed the role of memory B cells and interferon (IFN)-gamma signaling in TLS formation in TDLN and primary tumors.