PO.TB10.10 · 肿瘤生物学
Immune-active and mesenchymal endothelial programs define TLS presence in the tumor microenvironment
作者与单位
摘要 Abstract
Introduction: Tertiary lymphoid structures (TLSs) are ectopic lymphoid formations. In cancer, they promote antitumor immunity by supporting B-cell maturation, antibody production, and sustained T-cell activation. TLSs can convert immunologically non-inflamed tumors into inflamed ones. However, the vascular and molecular cues that govern TLS induction in human tumors remain poorly defined.
Methods: Formalin-fixed paraffin-embedded tissue sections from twelve primary lung adenocarcinomas were analyzed. Tumor-associated vasculature was histologically annotated and stratified into three categories based on TLS status: (1) noTLS (absence of TLS), (2) iTLS (presence of immature TLS), and (3) mTLS (presence of mature TLS). GeoMx spatial transcriptomics was performed on endothelial regions. Protein-level validation was conducted using sequential immunofluorescence on the COMET platform.
Results: Endothelial cells in noTLS regions showed high expression of COL5A1, COL3A1, FN1, ERRFI1, COL1A1, IFI6, SPP1, MDK, and BGN, whereas CXCL13 and CCL19 were enriched in mTLS. Gene-set analyses revealed that noTLS endothelium exhibited a myofibroblast-like, extracellular matrix-producing, EndoMT-associated program consistent with a fibrotic, immunosuppressive microenvironment. In contrast, mTLS endothelium displayed immune-activated signatures aligned with lymphoid organogenesis and fibroblastic reticular cell-like function. Receptor-ligand analysis showed preferential Wnt signaling in noTLS, while chemokine signaling dominated in mTLS. COMET immunofluorescence confirmed that FN1 was highly expressed in noTLS regions, whereas CXCL13 was highly expressed in mTLS.
Conclusion: Tumor endothelial cells display striking context-dependent plasticity. noTLS vasculature undergoes EndoMT and adopts a matrix-producing, immunosuppressive phenotype that may actively suppress TLS formation. Conversely, mTLS endothelium acquires immune-organizing properties that favor TLS maturation and lymphoid compartmentalization. These findings identify endothelial reprogramming as a potential therapeutic strategy to induce TLSs and enhance response to immune checkpoint blockade.
利益披露 Disclosure
S. Kure, None..
G. B. Pisoni, None..
S. Tabasum, None..
X. Li, None..
J. Li, None..
Y. Y. Yeo, None.
S. Jiang,
Elucidate Bio Inc Other, Board of Directors and Scientific Advisory Board.
Roche ), Other, Grant not related to this study.
Novartis ), Other, Grant not related to this study.
H. Olszewski, None..
N. C. Weaver, None..
K. L. Pfaff, None.
J. L. Weirather,
Elucidate Bio Employment.
I. D. Dryg, None.
S. J. Rodig,
Bristol Myers Squibb ).
Coherus Therapeutics ).
Novartis ).
Immunitas Therapeutics Other, Member of the SAB.
F. S. Hodi,
Bristol-Myers Squibb ).
Genentech/Roche ).
Novartis Other, an advisory board.
Gossamer Other, an advisory board.
Compass Therapeutics Other, an advisory board.
Apricity Other, an advisory board.
Iovance Other, an advisory board.
Immunocore Other, an advisory board.
Kairos Other, an advisory board.
Zumutor Other, an advisory board.
Curis Other, an advisory board.
AstraZeneca Other, an advisory board.
Corner Therapeutics Other, an advisory board.
Surface Other, an advisory board.
Bioentre Other, an advisory board.
Catalym Other, an advisory board.
Checkpoint Therapeutics Other, an advisory board.
Bicara Other, a board member.
Pieris Pharmaceutical a consultant.