PO.TB10.10 · 肿瘤生物学
免疫活化和间充质内皮程序界定肿瘤微环境中TLS的存在
Immune-active and mesenchymal endothelial programs define TLS presence in the tumor microenvironment
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
引言：三级淋巴结构(TLSs)是异位淋巴样形成物。在癌症中，它们通过支持B细胞成熟、抗体产生和持续的T细胞激活来促进抗肿瘤免疫。TLS可将免疫上非炎症性肿瘤转变为炎症性肿瘤。然而，在人类肿瘤中调控TLS诱导的血管和分子线索仍未充分界定。
方法：分析了来自12例原发性肺腺癌的福尔马林固定石蜡包埋组织切片。对肿瘤相关血管进行组织学标注，并根据TLS状态分为三类：(1) noTLS(无TLS)、(2) iTLS(存在未成熟TLS)和(3) mTLS(存在成熟TLS)。对内皮区域进行了GeoMx空间转录组学分析。使用COMET平台上的顺序免疫荧光进行了蛋白质水平验证。
结果：noTLS区域的内皮细胞表现出COL5A1、COL3A1、FN1、ERRFI1、COL1A1、IFI6、SPP1、MDK和BGN的高表达，而CXCL13和CCL19在mTLS中富集。基因集分析显示，noTLS内皮表现出肌成纤维细胞样、产生细胞外基质、与EndoMT相关的程序，与纤维化、免疫抑制性微环境一致。相反，mTLS内皮显示出与淋巴器官发生和成纤维网状细胞样功能一致的免疫活化特征。受体-配体分析显示noTLS中优先存在Wnt信号，而mTLS中趋化因子信号占主导。COMET免疫荧光证实FN1在noTLS区域高表达，而CXCL13在mTLS中高表达。
结论：肿瘤内皮细胞表现出显著的情境依赖性可塑性。noTLS血管经历EndoMT，并采取产生基质的、免疫抑制性的表型，可能主动抑制TLS形成。相反，mTLS内皮获得有利于TLS成熟和淋巴区室化的免疫组织化特性。这些发现将内皮重编程确定为诱导TLS并增强对免疫检查点阻断反应的一种潜在治疗策略。
查看英文原文 English 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.