4P - Spatially resolved transcriptome elucidates bidirectional tertiary lymphoid structure interacts with tumor microenvironment of non-small cell lung cancer

Background

The presence of tertiary lymphoid structure has a significant correlation with the lung cancer patient's response to immune checkpoint inhibitors. Nonetheless, the developmental characteristics of TLS and their surrounding tumor microenvironmental features in the primary tumor have not been elucidated comprehensively.

Methods

We utilized spatially resolved transcriptome and single-cell RNA sequencing to examine the molecular signatures and the essential cell types of TLS during its maturation process in the tumor microenvironment. Additionally, multiplex immunofluorescence staining and whole transcriptome sequencing were performed for validation.

Results

We categorized 406 potential TLSs into four states: pre-TLS, primary TLS, mature TLS, and aging TLS - based on their spatial molecular characteristics. The high expression of FDCSP in follicular DCs is a novel marker to promote TLS maturation by specifically binding to activated B cells. Three types of receptor-ligand interactions in mature and aging TLS could predict the prognosis in early-stage LUAD. Interestingly, aging TLS with significantly upregulated FOXP3 and TOX2 could limit anti-tumor immunity. Additionally, the molecular characteristics of aging TLS showed a lower expression of a group of CC chemokine ligands compared to mature TLS, which could potentially lead to a weaker anti-tumor response. We also observed an increase in tumor proliferation activity in the periphery of the aging TLS region. One approach to reverse the anti-tumor activity of aging TLS to that of mature TLS could be to increase the concentration of environmental chemokines while simultaneously blocking the upregulation of TIGIT in aging TLS.

Conclusions

Those results demonstrated that the condition of TLS was influenced by the neighboring tumor microenvironment in the early-stage LUAD. And the conventional mature TLS would eventually reach a biologically aged state in the same tumor microenvironment. By regulating chemokine signaling in the aging TLS's surrounding environment, it could potentially serve as an adjuvant therapy to enhance the antitumor activity of immune elements in resectable LUAD patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

TJMUCH and BGI.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.