Bekkhus Tove, Martikainen Teemu, Olofsson Anna, Franzén Boger Mathias, Vasiliu Bacovia Daniel, Wärnberg Fredrik, Ulvmar Maria H
The Beijer Laboratory, Department Immunology, Genetics and Pathology, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala University, 75185 Uppsala, Sweden.
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, 41345 Gothenburg, Sweden.
Cancers (Basel). 2021 Jan 8;13(2):211. doi: 10.3390/cancers13020211.
The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers.
肿瘤引流淋巴结（TDLNs）是诱导肿瘤免疫的主要部位。它们也是常见的转移部位，这表明肿瘤诱导的机制可以破坏抗肿瘤免疫反应并促进转移播散。高内皮微静脉（HEVs）与表达CCL21的成纤维网状细胞（FRCs）对于淋巴细胞募集进入淋巴结至关重要。我们建立了多色抗体组合用于评估乳腺癌（BC）患者TDLNs中的HEVs和FRCs。我们的数据显示，浸润性BC患者的HEVs表现出广泛的结构和分子重塑，包括血管扩张、内皮变薄以及HEV标志物PNAd的不连续表达。HEVs的重塑与血管周围FRCs中CCL21的失调以及CCL21饱和淋巴细胞的积累有关，我们将其与FRCs中CCL21结合硫酸乙酰肝素的丧失联系起来。这些变化在非浸润性BC患者和无癌器官供体的淋巴结中很少见或不存在，并且与淋巴结转移无关。因此，TDLNs内核心基质和血管功能的转移前失调反映了BC中原发性肿瘤的侵袭性。这增加了对癌症诱导的免疫反应扰动的理解，并为TDLNs中血管和基质变化作为潜在生物标志物的前景开辟了道路。
