Cancer cells regulate lymphocyte recruitment and leukocyte-endothelium interactions in the tumor-draining lymph node.
The physiologic function of the secondary lymphoid organs to recruit large numbers of naïve lymphocytes increases the probability that antigens encounter their rare, sometimes unique, specific T lymphocytes and initiate a specific immune response. In peripheral lymph nodes (LNs), this recruitment is a multistep process, initiated predominantly within the high endothelial venules (HEVs), beginning with rolling and chemokine-dependent firm adhesion of the lymphocytes on the venular endothelium surface. We report here that, in C57BL/6 mice, the recruitment of naïve lymphocytes is impaired in LNs draining a B16 melanoma tumor. Intravital microscopy analysis of the tumor-draining LNs revealed that this effect is associated with an important defect in lymphocyte adhesion in the HEVs and a progressive decrease in the expression of the LN chemokine CCL21. In parallel with these effects, the tumor up-regulated, essentially through a P-selectin-dependent mechanism, the rolling and sticking of circulating polymorphonuclear cells within the LN low-order venules where few rolling and sticking events are usually observed. These effects of the tumor were independent of the presence of metastasis into the LN and occurred as long as the tumor developed. Together, these results indicate that the tumor proximity disturbs the LN physiology by modifying the molecular, spatial, and cellular rules that usually control leukocyte-endothelium interactions into the peripheral LNs. In addition, they emphasize a new role for the low-order venules of the peripheral LNs, which compared with the HEVs, seem to be the preferential port of entry for cells linked to inflammatory processes.
Carrière
Virginie
V
Laboratoire de Biologie Vasculaire, Equipe labellisée La Ligue 2003, Institut de Pharmacologie et de Biologie Structurale, CNRS UMR 5089, Toulouse, France.
Colisson
Renaud
R
Jiguet-Jiglaire
Carine
C
Bellard
Elisabeth
E
Bouche
Gérard
G
Al Saati
Talal
T
Amalric
François
F
Girard
Jean-Philippe
JP
M'Rini
Christine
C
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000166:cytology* / Q000276:immunology*; D005260:Female; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008198:Lymph Nodes / Q000276:immunology*; D008207:Lymphatic Metastasis / Q000276:immunology; D008214:Lymphocytes / Q000502:physiology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019007:P-Selectin / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D019041:L-Selectin